GP120: Biologic Aspects of Structural Features

Size: px
Start display at page:

Download "GP120: Biologic Aspects of Structural Features"

Transcription

1 Annu. Rev. Immunol : Copyright c 2001 by Annual Reviews. All rights reserved GP120: Biologic Aspects of Structural Features Pascal Poignard, Erica Ollmann Saphire, Paul WHI Parren, and Dennis R. Burton Departments of Immunology and Molecular Biology, The Scripps Research Institute, North Torrey Pines Road, La Jolla, California 92037; poignard@scripps.edu, burton@scripps.edu Key Words HIV-1, HIV envelope protein gp120, HIV antibodies, neutralization, AIDS vaccines Abstract HIV-1 particles are decorated with a network of densely arranged envelope spikes on their surface. Each spike is formed of a trimer of heterodimers of the gp120 surface and the gp41 transmembrane glycoproteins. These molecules mediate HIV-1 entry into target cells, initiating the HIV-1 replication cycle. They are a target for entry-blocking drugs and for neutralizing Abs that could contribute to vaccine protection. The crystal structure of the core of gp120 has been recently solved. It reveals the structure of the conserved HIV-1 receptor binding sites and some of the mechanisms evolved by HIV-1 to escape Ab responses. The gp120 consists of three faces. One is largely inaccessible on the native trimer, and two faces are exposed but apparently have low immunogenicity, particularly on primary viruses. We have modeled HIV-1 neutralization by a CD4 binding site monoclonal Ab, and we propose that neutralization takes place by inhibition of the interaction between gp120 and the target cell membrane receptors as a result of steric hindrance. Knowledge of gp120 structure and function should assist in the design of new drugs as well as of an effective vaccine. In the latter case, circumventing the low immunogenicity of the HIV-1 envelope spike is a major challenge. INTRODUCTION To combat the spread of HIV-1 infection, new treatments and an effective vaccine are greatly needed. The HIV-1 envelope glycoproteins, gp120 and gp41, are important molecules for both therapeutic and prophylactic approaches. First, they mediate HIV entry and therefore are a potential target for drugs aimed at blocking the first step of the viral replication cycle. Second, the envelope glycoproteins are the target of neutralizing Abs and could be the basis of the humoral component of a vaccine. Recently, great progress has been made in understanding HIV-1 entry and structure/function relationships in viral envelope glycoproteins. A compound that blocks HIV-1 entry has demonstrated convincing efficacy at controlling HIV /01/ $

2 254 POIGNARD ET AL replication in patients, providing a proof of principle for this class of therapeutics. Furthermore HIV-1 envelope glycoproteins have been crystallized, bringing new insights for drug and vaccine design. This review summarizes the recent progress in the understanding of the gp120 structure and function, and focuses on our view of the area since a number of more general reviews have been published previously (1 3). HIV-1 ENVELOPE GLYCOPROTEINS HIV is an enveloped virus decorated with spikes on its surface that are essential for viral entry into target cells. These envelope spikes consist of a protein complex that comprises a cell-surface attachment glycoprotein, gp120, and a membrane spanning protein, gp41. Virus binding to the target cell takes place via a sequential interaction between gp120 and HIV cellular receptors: the CD4 molecule and members of the chemokine family receptors, termed HIV coreceptors. The CD4 molecule is a member of the immunoglobulin superfamily, mainly expressed on T lymphocytes, macrophages, and dendritic cells. Binding of gp120 to CD4 is not sufficient to permit HIV entry, which, in addition, requires the interaction of the gp120 envelope glycoprotein with a member of the chemokine receptor family (4). Chemokine receptors are seven transmembrane domain proteins that contain four extracellular domains: an amino-terminal domain and three extracellular loops. The two major coreceptors used by HIV-1 to enter target cells are CCR5 (5 8) and CXCR4 (9). CCR5 functions as the principal coreceptor for macrophage tropic strains (R5 strains), whereas CXCR4 is used by T tropic strains (X4 strains). Dual tropic HIV-1 strains (R5X4 strains) can use both coreceptors. Other coreceptors of less well understood importance in vivo have been reported (4). The tropism of envelope glycoproteins for either coreceptors depends on the ability of gp120 to interact directly with these receptors. The importance of CCR5 has been demonstrated by the discovery that a homozygous 32 bp deletion in the CCR5 gene confers resistance to HIV infection (10, 11). Failure of most individuals homozygous for the CCR5 32 deletion to become infected suggests that X4 viruses are inefficient at establishing an infection in a naïve host (8). Indeed R5 viruses are prevalent during the early phase of infection (12). Furthermore, heterozygosity for the CCR5 32 deletion delays progression to disease, probably because of a decrease of coreceptor expression (13 16). This observation suggests that interference with the viral entry process could be beneficial to infected individuals. GP120 STRUCTURE The HIV-1 envelope glycoprotein complex is initially produced as a single chain glycoprotein precursor, gp160, which is cleaved by a cellular protease. Gp160 cleavage yields the cell-surface attachment glycoprotein, gp120, and the membrane spanning protein, gp41. The two HIV envelope glycoproteins are noncovalently

3 HIV-1 GP120 STRUCTURE AND FUNCTION 255 linked and assemble into an oligomer, most likely a trimer (see below), of gp120- gp41 heterodimers that is expressed at the cell surface and then, following viral budding, at the virion surface (17, 18). The surface envelope glycoprotein gp120 is a heavily glycosylated protein with carbohydrates accounting for about 40% to 50% of the molecular weight. It is composed of five constant regions (C1 C5) interspersed with five variable regions (V1 V5) (19, 20). Until recently, little information on gp120 structure was available. The only clues came from functional analysis of variant viruses, topographical mapping based on monoclonal Ab binding analysis, crystallographic and NMR studies of small portions of gp120, and molecular modeling with reference to homologous viral proteins of known structure. These studies suggested that the conserved regions of gp120 form a central core, whereas the variable regions, with the exception of V5, are bracketed with cysteine disulfide bonds and form four loops that emanate from the surface of the protein (for review, see 21). The understanding of gp120 structure advanced remarkably with the resolution, by the groups of W Hendrickson and J Sodroski of the crystal structure of a complex formed between the gp120 core, the membrane distal 2 domains of the CD4 molecule and an antibody Fab fragment (22). We summarize below the main features of the gp120 crystal structure, but for an exhaustive description the reader is referred to the excellent original papers and accompanying reviews (22 24). To obtain crystals that diffracted with sufficient resolution, a gp120 core molecule was used that lacks the variable loops V1-V2 and V3 and amino- and carboxyterminal sequences and that had been enzymatically stripped of over 90% of its carbohydrates. The loops were replaced with the tripeptide linker Gly-Ala-Gly. The final deglycosylated V3, V1-V2 gp120 core retains 67% of the envelope amino acid content of the full-length molecule and has a molecular weight of 35 kda. Despite the modifications, the core retains structural integrity as shown by its ability to bind CD4 and to interact with a number of antibodies at levels comparable to the full-length molecule (25). Although the variable regions V3, V1-V2 are deleted, the core still contains some variable fragments the V4 and V5 loops as well as surface loops termed LD and LE. The crystal structure at 2.5 Å resolution revealed that the gp120 core is composed of 25 β-strands, 5 α-helices, and 10 loop segments and that it folds into an heart-shaped globular structure with dimensions of nm. It is interesting that the gp120 structure is unrelated to any previous protein structure described. The core is formed of an inner domain and an outer domain that are linked by a four-stranded sheet termed the bridging sheet. Among different clades of HIV-1, the inner domain is more conserved than the outer domain. The crystal structure reveals that all three domains of the gp120 core are important for CD4 and coreceptor binding. The Receptor Binding Sites on gp120 The receptor binding sites are potential targets for therapeutic intervention as they are likely to be conserved among different strains of HIV and need to be exposed on the gp120 surface at least transiently for the virus to enter the target cell.

4 256 POIGNARD ET AL The CD4 Binding Site On gp120, the CD4 binding site is located in a depression formed at the interface of the outer and inner domains with the bridging sheet (22). Surprisingly, half of the residues of gp120 that contact CD4 do so only through main-chain atoms, which might help in escape from Abs as discussed below. Figure 1 shows the footprint of CD4 binding on the gp120 core, with proposed crucial contact residues highlighted in orange. The surface of interaction between gp120 and CD4 is large, covering 800 Å 2 on gp120 and 740 Å 2 on CD4. On gp120, the contact surface includes two unusually large cavities. The larger cavity (about 280 Å 3 ) is shallow and filled with water molecules. It is lined with gp120 residues that do not form many direct contacts with CD4. This allows variability to occur within the otherwise conserved CD4 binding site. The second cavity (about 150 Å 3 ) is hydrophobic, approximately spherical, and is deeply buried within gp120. It is located at the interface between the three domains and is lined by highly conserved residues. Upon CD4 ligation, the entrance of this cavity is plugged by Phe43 of CD4, which is crucial for the gp120-cd4 interaction. The Coreceptor Binding Sites The gp120 residues involved in the coreceptor CCR5 binding site were characterized by analysis of the binding of a panel of gp120 mutants to CCR5 (26). Site-directed mutagenesis of gp120 was carried out using structural information from the crystal structure of gp120 and in particular from knowledge of the contact residues of gp120 and the CD4-induced (CD4i) Ab 17b. The epitope recognized by this Ab (see below) overlaps the CCR5 binding site as suggested by the greater exposure of both the CCR5 binding site and the 17b epitope upon CD4 binding to gp120 and by the competition of CD4i Abs for the binding of gp120 to CCR5 (27). The results of the mutagenic analysis suggest that the CCR5 binding site is one of the most highly conserved surfaces on the gp120 core, even more conserved than the CD4 binding site (26). The CCR5 binding site is located on the gp120 core in relatively close proximity to the CD4 binding site (Figure 1). The residues involved in CCR5 binding are found near or within the bridging sheet on the gp120 core. Some of these residues likely contact the coreceptor molecule directly. Residues of the V3 loop are probably involved in CCR5 binding, potentially forming a discontinuous binding site with the conserved core elements, but these residues are absent from the crystal structure. The surface of the CCR5 binding site on the gp120 core is highly basic. This should favor interaction with the acidic N-terminal portion of the coreceptor (28 30). Importantly, exposure of the highly conserved coreceptor binding site requires that gp120 first binds CD4 (22, 26). Models of the gp120 oligomer suggest that, after CD4 ligation, the bridging sheet is oriented toward the target cell (24, 31). Experimental data suggest that binding to CD4 leads to the repositioning of the V1-V2 loop and to the exposure or the formation of the coreceptor binding site (32). However, other gp120 conformational changes must also be involved as coreceptor binding of a V1-V2 loop-deleted gp120 is still CD4 dependent (27).

5 HIV-1 GP120 STRUCTURE AND FUNCTION 257 As described earlier, there are two principal HIV-1 coreceptors CCR5 and CXCR4. The binding sites of these two coreceptors share characteristics such as increased exposure upon CD4 binding and competition with CD4i Abs and anti-v3 loop Abs for binding to gp120. Furthermore, a simple V3 substitution can convert a CXCR4-using virus into one using CCR5 (33, 34). It is then likely that both coreceptors interact with a similar region of gp120, but they may not share contact residues. Some reports suggest that the affinity of gp120 for CXCR4 and for CCR5 may be different. Monomeric gp120 from R5 viruses binds poorly in the absence of soluble CD4, whereas monomeric gp120 from X4 viruses can bind CXCR4 with detectable affinity (27, 35). CD4-independent viruses that possess a constitutively exposed coreceptor binding site on the gp120 surface have been described (34 37). However, all HIV primary isolates described to date are CD4 dependent, and the relevance of such CD4-independent viruses in vivo is unknown. Of note, multiple regions of the coreceptor, including the N terminus and the extracellular loops are involved in the gp120-coreceptor interaction (48). Furthermore diverse virus strains differ in their relative dependence on receptor domains, showing that the virus is flexible in its interaction with the coreceptor (38). Other Potentially Conserved Exposed Sites on gp120 It has recently been demonstrated that heparan sulfate can influence the binding of HIV to some cells. Mondor et al have shown that binding to HeLa cells is CD4 independent but depends on an interaction with heparan sulfate at the cell surface (39). The role of heparan sulfate in vivo is unclear especially as the main target cells for HIV-1, CD4 T cells, and macrophages express little heparan sulfate on their surface. The ability to interact with heparan sulfate has been reported to be specific for X4 viruses. Moulard et al have shown that gp120 binding to heparan sulfate is dependent on coreceptor usage (40). Gp120 molecules from X4 and R5X4 viruses bind polyanions strongly, whereas R5 gp120 do not. The interaction with polyanions is mainly mediated by the V3 loop, and this interaction is followed by a second weaker interaction probably with the coreceptor binding region. This interaction resembles the gp120-coreceptor interaction, involving the V3 loop and the coreceptor binding site, but is limited to X4 and X4R5 gp120 molecules. The relevance of this observation in vivo is unclear. HIV-1 may use binding to polyanion as an initial means of attachment to the cell surface before forming a specific stronger interaction with CD4 and coreceptor. Another interaction of gp120 with a cell surface molecule has been described recently and may be of greater relevance for HIV-1 pathogenesis. Previously gp120 had been shown to bind with high affinity to a C-type lectin isolated from a placental cdna library (41). This molecule is now known to be a dendritic cell-specific lectin (DC-SIGN) (42). Geijtenbeek et al reported recently that this molecule is not used by HIV-1 as an entry receptor but may facilitate the capture and transport of HIV from mucosal surfaces to secondary lymphoid organs rich in T cells (43). Surprisingly, DC-SIGN can enhance infection of T cells in trans. The interaction of DC-SIGN with gp120 is independent of binding to CD4 and CCR5. Further, as

6 258 POIGNARD ET AL mannan blocks the binding of DC-SIGN to gp120, it is probable that it interacts with carbohydrate moieties on gp120. However, that the lectin domain interacts with the polypeptide backbone of gp120 cannot be ruled out. THE ENVELOPE SPIKE The gp120-gp41 heterodimers associate in a trimer to form spikes at the virus surface that we term the native trimer. As discussed below, the oligomerization of the envelope glycoproteins has important consequences for their antigenicity and immunogenicity. The structure of the envelope spike is unknown. Modeling of the entire oligomer, including gp41, is not possible as the structure of gp41 in its gp120-associated state is not known. By analogy with the HA 2 protein of influenza virus, gp41 is currently thought to exist in a metastable non-coiled-coil conformation when associated with gp120 (44). A model of gp120 trimer has been proposed (24, 31). This model suggests that the surface of the gp120 trimer is roughly hemispherical. The inner domain of gp120 faces the trimer axis, whereas the outer domain is mostly exposed on the surface of the oligomer. The coreceptor binding site is close to the trimer axis and faces the target cell surface after CD4 ligation to gp120. The surface that faces the target cell is highly basic and includes the V3 loop. The model suggests that three CD4 molecules can bind obliquely to a gp120 trimer without steric interference. The envelope spikes have been studied by electronic microscopy. These studies show that on the viral particle the envelope spikes form densely arranged knobs (45, 46). The diameter of each knob is about 14 nm and its height is 9 to 10 nm. The knobs are organized on the virion according to a skew class of icosahedral symmetry (45, 46). The ultrastructural studies suggest that mature HIV particles are icosahedral, comprising 20 faces and 12 vertices, and possess about 72 spikes (45 47). This symmetry follows the organization of the underlaying matrix protein p17 Gag. Trimers of the matrix protein associate in a hexagonal network of icosahedral symmetry that forms a hole into which gp41 can insert, determining the position of each spike on the viral surface (48 51). Measurement of electronic microscopy images of the viral particle show that the distance from the center of one spike to the next is about 21 to 22 nm (45, 46, 51). HIV-1 ENTRY The HIV entry process is complex. The first step is the binding of the CD4 molecule to gp120 at the surface of the viral particle as shown in Figure 2. Experimental evidence and the recently published gp120 structure suggest that CD4 binding induces conformational changes within the bridging sheet as well as between this sheet and the inner and outer domains of gp120 (22, 52, 53). These conformational changes lead to the exposure or the formation of the high-affinity

7 HIV-1 GP120 STRUCTURE AND FUNCTION 259 coreceptor binding site (26). These rearrangements in gp120 involve a movement of the V1-V2 stem away from the underlying coreceptor binding site while the V3 loop may move toward this binding site (32). Binding of the coreceptor to gp120 results in further conformational changes that lead to gp41 activation into its fusion-active state. It is currently thought that, as discussed above, gp41 exists in a metastable non-coiled-coil conformation when associated with gp120 and that, similarly to influenza virus HA 2, gp41 uses the coiled-coil formation as a spring-loaded mechanism to bring the viral and cell membranes closer (44, 54, 55). It has been proposed that following coreceptor binding the envelope glycoprotein complex undergoes conformational changes that lead to the insertion of gp41 fusion peptide into the membrane of the target cell and to the formation of a prehairpin intermediate where gp41 is both a viral and a cell membrane protein. One study suggests that the prehairpin intermediate is induced rapidly after binding of gp120 to its receptors and has a lifetime of minutes (56). The prehairpin intermediate is followed by the formation of a gp41 coiled-coil structure, leading to the apposition of membranes and ultimately to fusion. The formation of the coiled-coil may lead to the dissociation of gp120 from gp41, the gp120 molecule possibly remaining anchored to the target cell membrane through CD4 and coreceptor binding. The fusion events are poorly understood, and how many gp41 trimers are required in order to form a fusion pore is not yet known. Of note, the mechanism of promotion of HIV-1 entry by DC-SIGN is not known. DC-SIGN might induce conformational rearrangements that enhance the interaction between gp120 and CD4 or the coreceptor or facilitate other entry steps (43). GP120 ANTIGENICITY AND IMMUNOGENICITY It has been long recognized that Abs can inhibit HIV-1 infectivity. Such Abs, termed neutralizing Abs, are directed against the envelope glycoproteins of HIV. Studies in animal models suggest that neutralizing Abs may be an important component of an efficient HIV vaccine ( ). However, it is proving extremely difficult to generate HIV-1 envelope molecules that elicit such neutralizing Abs. Knowledge of the HIV-1 envelope glycoproteins structure may help understanding of how HIV-1 has evolved to escape humoral immunity and may permit the design of more efficient vaccines. A number of reviews have recently discussed HIV-1 neutralization in a general way (1, 57); here we focus on structural aspects of the interaction of neutralizing Abs with HIV-1 envelope glycoproteins. Studies of the binding of monoclonal Abs to gp120 and of Ab cross-competition suggested the existence on gp120 of two faces (58, 59). These studies showed that neutralizing epitopes cluster on gp120 to form a surface that was termed the neutralizing face. By contrast, non-neutralizing epitopes cluster on another face on the gp120 core, forming a non-neutralizing face. Analysis of Ab binding to the envelope trimer expressed at the surface of HIV-infected cells suggested that the

8 260 POIGNARD ET AL non-neutralizing epitopes are not exposed on the oligomeric form of gp120, being hidden within the trimer (58, 60). Structural studies of gp120 have then confirmed the existence of a neutralizing and a non-neutralizing face predicted by Ab crosscompetition analysis (24, 59) and have revealed the presence of a third face, termed by Wyatt et al. the silent face (23). The Silent Face of gp120 The heavy glycosylation of gp120 has long been thought to contribute to reduction of protein epitope exposure and to enhance viral evasion from Ab (61). Indeed carbohydrate side chains scarcely induce Ab responses, as they appear to the immune system as self. It is interesting that the crystal structure of gp120 showed that most carbohydrates locate on a single face on the outer domain of the gp120 core (24). Models of gp120 trimerization suggest that this face is well exposed at the surface of the envelope oligomer (24, 31). The poor immunogenicity of this face has led to its designation as the silent face. The face also contains the variable loops V4, V5, LA, LC, LD, and LE. The Non-Neutralizing Face of gp120 This face induces a strong Ab response in infected individuals. However, Abs that bind epitopes belonging to this surface do not neutralize HIV-1. The nonneutralizing face corresponds to the inner domain of gp120 core and is relatively conserved (22). Analysis of Ab binding to gp120 trimer complexes expressed at the surface of infected cells as well as models of gp120 trimer suggest that this surface is buried within the gp120 trimer and is not exposed at the surface of the envelope oligomeric complex on the viral particle (24, 31, 60). Therefore, Abs that bind to epitopes on the non-neutralizing face cannot bind to virions and have no neutralizing activity. This view has been disputed by reports suggesting that some non-neutralizing epitopes could be exposed at the surface of the oligomeric gp120 on the virion surface (62 65). As explained below, in view of the probable mechanism of neutralization, we favor the hypothesis that non-neutralizing epitopes correspond to epitopes that are not exposed on the gp120 trimer and that all exposed epitopes are neutralizing. As the non-neutralizing face is well exposed at the surface of soluble monomeric gp120, it has been proposed that such Abs are elicited by gp120 shed from the viral particles and/or infected cells. However, as the gp160 precursor and monomeric gp120 share similar antigenicity, an alternative is that non-neutralizing Abs are elicited in response to gp160 found in quantities in debris of dying HIV-infected cells (66). Indeed the affinity of a number of human Abs is greater for gp160 than for gp120, suggesting that the former may be the eliciting Ag in vivo. It could also be hypothesized that such Abs are raised against viruses that bear partially shed spikes, exposing monomeric gp120 on their surface. Such particles would indeed be stronger immunogens than free monomeric gp120 (67).

9 HIV-1 GP120 STRUCTURE AND FUNCTION 261 The Neutralizing Face of gp120 To replicate, HIV-1 must interact with its receptors on target cells. As a consequence, part of the surface of gp120 has to be both exposed and conserved. The neutralizing face corresponds to this surface. However, HIV has evolved astute mechanisms to escape the Ab response, and the gp120 structure shows that this face is still relatively occluded (22, 24). In particular, the two most conserved regions, the receptor binding sites, are poorly accessible to Abs. Furthermore, the neutralizing epitopes are mainly accessible on viruses that have been adapted to immortalized T cell lines (T cell line adapted or TCLA isolates). These viruses are very sensitive to neutralization. By contrast, primary isolates, i.e. viruses that have been passaged only a limited number of times on activated primary lymphocytes, are much less sensitive to Ab neutralization (68). Differences in the quaternary structure of the envelope complex can presumably explain the differences between TCLA viruses and primary isolates to neutralization. The gp120 trimer of TCLA adopts a relatively open conformation, allowing the exposure in particular of the CD4 binding site, the coreceptor binding site, and the V3 loop. In contrast, it has been proposed that the primary isolate trimeric complex has a more closed conformation, reducing acceessibility of the receptor binding sites and preventing the binding of neutralizing Abs (57, 69 71). Primary isolates are significantly more representative of patient isolates than TCLA viruses. An ideal vaccine should essentially induce Abs that can neutralize a broad range of primary isolates. Only two broadly neutralizing anti-gp120 monoclonal Abs, both of human origin, have been described to date (72). The first Ab, b12, binds to an epitope overlapping the CD4 binding site (73 75). The second Ab, 2G12, recognizes a unique epitope located on the outer domain of gp120 (76). Below is a description of the neutralizing epitopes on gp120. The b12 and 2G12 epitopes are important for the neutralization of primary and TCLA viruses. The CD4 binding site in general, the variable loops, and the coreceptor binding site are more significant for TCLA viruses. CD4 Binding Site; The b12 Epitope The CD4 binding site revealed by the crystal structure of CD4 bound-gp120 has been described above. However, it should be stressed that the CD4 binding site conformation in this structure may not correspond to the one recognized by Abs. Indeed, as explained above, binding of CD4 to gp120 induces important conformational changes in the envelope glycoprotein. The CD4 binding site, as seen by Abs and by the immune system, is unliganded and might adopt a different conformation than the one described in the crystal structure of CD4-liganded gp120. Nevertheless, the structure of an unliganded gp120 would then be more informative in understanding more thoroughly immunogenicity from the perspective of vaccine design. The gp120 crystal structure that has been determined gives useful information on the epitopes of CD4 binding site Abs (22). As expected, residues critical for Abs that compete with CD4 binding locate within the CD4 binding domain. The location, close to the coreceptor binding site, of residues Asp 368 and Glu 370, known to be important for the binding of most CD4 binding

10 262 POIGNARD ET AL site Abs (24, 77), shows that these epitopes also overlap the coreceptor binding site. This explains why anti-cd4 binding site Abs tend to compete with CD4i Abs (59, 78). Interestingly, the structure of CD4-bound gp120 reveals some of the features that HIV has evolved to escape anti-cd4 binding site Abs despite the need to keep this region conserved and exposed enough for receptor ligation. The first difficulty for Abs is to access the CD4 binding site recessed within the gp120 core. Indeed, the Fab of an Ab molecule is wider than CD4 (two Ig domains compared to one). In addition the binding site is flanked by variable and glycosylated regions that will likely diminish its effective immunogenicity. The large hydrophilic cavity of the CD4 binding site tolerates gp120 mutations, and this may facilitate viral escape from anti-cd4 binding site Abs. Some of the residues of gp120 that contact CD4 do so through their main-chain atoms. As Abs mostly contact residues via their side chains, this may permit the variation of residues involved in receptor binding and the escape from neutralizing Ab without detrimental effects on CD4 binding. Finally, the CD4 binding site is partially masked by the V1-V2 loop (22, 32). Despite all these considerations, a number of Abs directed against the CD4 binding site neutralize TCLA viruses, suggesting that their epitopes are relatively well exposed on the virion surface (68). However, only the anti-cd4 binding site Ab b12 neutralizes a broad range of primary isolates (72). This Ab differs from all the other anti-cd4 binding site Abs described to date by its sensitivity to V1-V2 loop deletion (75). It is not known whether the Ab contacts the V1-V2 loop or if the sensitivity is only due to an indirect effect of conformational rearrangements following V1-V2 deletion. Analysis of Ab competition studies showed that b12 is the anti-cd4 binding site Ab that is most sensitive to anti-v2 competition, which might suggest that b12 contacts the V1-V2 loop (59). The proposed b12 contact residues, as determined by mutagenesis (75), are shown in Figure 1. It should be restated that this structure corresponds to the CD4-liganded gp120 and that gp120 may adopt another conformation prior to ligation. The 2G12 Epitope The 2G12 epitope is a unique neutralization site located on the outer domain of gp120 (Figure 1). 2G12 binding is sensitive to deglycosylation (76). It is impaired by mutations that alter N-linked carbohydrate sites localized in the C2, C3, V4, and C4 regions (76). This Ab can neutralize a broad range of TCLA and primary isolates (72, 79), and it is therefore likely that 2G12 binds, at least to some extent, to carbohydrate structures that are well conserved between isolates. Interestingly, although it is potently neutralizing, 2G12 does not interfere with CD4 and coreceptor binding. This Ab specificity is uncommon in sera from HIV-1-infected individuals (76). Variable Loops The V3 loop is a good TCLA isolate neutralizing epitope (1). Some anti-v3 loop Abs have a limited activity against particular primary isolates. However, primary isolates are in general poorly neutralized by anti-v3 loop Abs (72). The V3 loop is probably located close to the coreceptor binding site.

11 HIV-1 GP120 STRUCTURE AND FUNCTION 263 Consistently anti-v3 Abs block coreceptor binding to gp120 (80). The V3 loop is absent from the published gp120 crystal structure. The structure of V3 loop peptides conjugated with monoclonal Abs suggest that the V3 loop can adopt at least two different conformations (81). One of these two conformations was found three times for three different monoclonal Abs, suggesting that this conformation might be conserved (R Stanfield, personal communication). As one of these Abs can neutralize some primary isolates, this V3 loop conformation may be conserved among some primary isolates. Overall, however, the variability of the V3 loop conformation on gp120 or envelope trimer remains unclear. The importance of V1-V2 loop epitopes for neutralization, in particular of primary isolates, remains uncertain. The neutralizing potency of the V1-V2 Abs described to date is quite limited (82) (J Moore, personal communication), and the variability of the V1-V2 loop remains an important obstacle for broad neutralization. CD4 Induced Epitope CD4 induced (CD4i) Abs bind to gp120 with greater affinity when gp120 is complexed to CD4 (78). As discussed before, these Abs recognize an epitope that overlaps the coreceptor binding site. The published gp120 crystal structure reveals the interaction of the Fab fragment of the CD4i Ab 17b with CD4 bound-gp120 (22). The Fab fragment covers a surprisingly small surface of 455 Å of gp120, centered on residues of the bridging sheet and the stem of the V1-V2 loop and oriented toward the target cell membrane. The coreceptor binding site is the most conserved surface of gp120 and could be a promising target for neutralization (26). However, mab 17b neutralizes TCLA viruses very poorly and primary isolates not at all. It appears that the 17b epitope is largely masked prior to CD4 binding by the V1-V2 loop. Furthermore, in contrast to binding of soluble CD4, the binding of cell surface CD4 to virus does not appear to make available the epitope to binding by 17b to allow neutralization. Presumably the binding of gp120 to cell surface CD4 brings the viral envelope complex so close to the target cell that although this region is accessible to coreceptor, it is not accessible to Ab. It may be that HIV-1 has evolved to use CD4 to provide a means to hide the conserved coreceptor binding site in order to prevent Ab neutralization (34). Gp120 Structure and Ab Neutralization The recent determination of the crystal structures of the neutralizing Ab b12 (E Ollmann Saphire, manuscript in preparation) and of gp120 (22) gives us the opportunity to model the interaction of gp120 with this neutralizing Ab. As shown in Figure 3, we modeled the binding of b12 to the gp120 oligomer at the surface of a viral particle about to encounter a target cell. The crystal structure of the b12 Ab shows that, consistent with previous knowledge, the Ab could extend about 18 nm from the tip of one Fab to the other and about 16 nm from the tip of a Fab to the tip of the Fc; the individual Fab and Fc fragments have dimensions of about nm and nm, respectively. Furthermore the

12 264 POIGNARD ET AL hinge region gives a high flexibility to the Ab molecule. Gp120 on the other hand adopts a more compact conformation; the core has dimensions of nm (22). As discussed above, the gp120 trimer at the surface of the virus forms a knob of 14nm diameter and about 9 to 10 nm height above the viral membrane. The space occupied by an Ab molecule thus compares to or even surpasses the space occupied by a gp120 trimer. In addition, the spikes are equally distributed on the viral surface every 21 nm, which means that the outer edge of a spike approaches within 7 nm of its neighbors (45, 51). Therefore, considering the space occupied by the Ab and the close proximity of the spikes, when an Ab molecule is bound to gp120, the Fc (and possibly the free Fab) is likely to project from the virus surface as a result of steric hindrance and geometric constraints (Figure 3). The structure solved for CD4 suggests that the membrane distal domains are parallel to the cell surface and that the first domain probably extends no further than 7 nm from the cell surface. Then, taking into account the respective sizes of the envelope trimer, the Ab and the CD4 molecule, it becomes unlikely that, when b12 Ab molecules are bound to an array of gp120 spikes, the viral and cellular membranes can approach close enough for the binding of gp120 to CD4 to take place, even though free CD4 binding sites may still be available on the spikes in question (Figure 3). We have previously shown that neutralization of HIV-1 by Abs against gp120 is determined primarily by occupancy of sites on the virion, irrespective of the epitope recognized (83). The molecular model shown in Figure 3 is in agreement with these results and refines the model that we have previously proposed (83). It is apparent that steric constraints will be roughly similar wherever an Ab molecule is attached to the gp120 trimer and will probably hinder further interaction with cellular receptors. This view is consistent with the inhibition of virus attachment to target cells observed for different anti-gp120 Abs against distinct epitopes (84, 85). The orientation of gp120 within the trimer suggests that the bivalent binding of an Ab to two gp120 molecules within the same trimer would require an extreme flexibility of the molecule, and this is unlikely (31). However, the short distance separating the viral spikes certainly permits bivalent binding of Abs to gp120 molecules belonging to different spikes, which would lead to increased avidity of the Ab. In a recent review we calculated the stoichiometry of HIV neutralization, based on a comparison of the neutralization behavior of HIV-1 with a number of other viruses and on the work of Schönning et al (2, 86). It was determined that the attachment of approximately 70 IgG molecules per virion is required for neutralization, which is equivalent to about one IgG molecule per spike (2). Neutralization of HIV-1 is therefore suggested to be the result of coating of the viral surface with Ab molecules to a critical density. In the model that we propose, any epitope exposed on the envelope spike can mediate neutralization as long as the critical coating density can be achieved. On the gp120 moiety of primary isolate envelope spikes, only two neutralizing epitopes are known to be exposed, forming the small neutralizing face shown in Figure 1. It should be noted that the term neutralizing

13 HIV-1 GP120 STRUCTURE AND FUNCTION 265 face can be misunderstood. It simply defines the area to which neutralizing Abs have been isolated to date and does not imply that Abs against the silent face cannot be neutralizing. However, under normal circumstances Abs against the latter region are not induced because of tolerance to carbohydrates. Ab 2G12 appears to be an exception and, in a sense, it could equally well be viewed to recognize the silent face as the neutralizing face. VACCINE DESIGN How can structural information help us design a vaccine that induces a strongly neutralizing Ab response? The structure of gp120 suggests that the virus escapes the Ab response first by burying much of the envelope glycoprotein surface (the non-neutralizing face), and second by decreasing the immunogenicity of the exposed surfaces (the neutralizing face and the silent face) on the envelope spike. Immunization with monomeric gp120, where the non-neutralizing face and the N- and C-terminal parts that interact with gp41 are exposed, has yielded Abs that bind to monomeric gp120 but not to the native oligomer and in particular not to the native oligomer of primary isolates (68). These Abs are consequently non-neutralizing. Immunization with the native envelope trimer may force the immune system to focus on the neutralizing epitopes exposed on the surface of the trimer, leading to the production of neutralizing Abs. Different approaches are possible. Virions chemically inactivated by modification of the nucleocapsid zinc finger motifs conserve a native conformation of the envelope oligomers and could be used for immunization (87). Attempts to produce stable soluble envelope glycoprotein trimers that conserve a native conformation are currently in progress, and some approaches may be promising. Yang et al have introduced GCN4 trimeric helices at the C-terminus of a soluble form of the envelope glycoprotein in order to stabilize the trimerization (88, 89). Binley et al have proposed the addition of cysteines into the envelope glycoproteins in order to permit the creation of disulfide bridges between gp120 and gp41 and the stabilization of the gp120-gp41 interaction (90). These approaches may be impaired by the low immunogenicity of the envelope trimer; modifications of gp120 might be required in order to increase immunogenicity. Removal of carbohydrates has been proposed to lead to greater immunogenicity and to the production of a better neutralizing Ab response (91). Removal of variable loops may also permit the exposure of otherwise hidden conserved surfaces. The difficulty with these approaches will be to increase immunogenicity without altering the antigenicity of the oligomeric gp120. This might prove difficult to achieve. Other approaches may be required. According to the model of neutralization we have championed, any exposed surface on the trimer is a potential neutralizing epitope. The silent face is a well-exposed surface, with very low immunogenicity in part because of its heavy glycosylation. However, gp120 possesses carbohydrate moieties that are conserved among isolates as shown by the broad neutralization

14 266 POIGNARD ET AL obtained with the 2G12 Ab (24, 72). A better understanding of gp120 carbohydrates and circumvention of their low immunogenicity could in principle make the HIV silent face a target for neutralizing Abs. If the spike immunogenicity problem cannot be solved, we may have to look beyond HIV-1 surface envelope proteins and to envisage the use of mimotopes (92). Approaches based on available potent neutralizing Abs can be proposed. Complementary molecules could be selected from protein fragment libraries or retroviral libraries or designed from the knowledge of Ab structure. Finally, approaches that aim at increasing the Ab response in general, such as dendritic cell-targeted immunization, may have to be coupled to the approaches described above in order to raise strong neutralizing Ab responses. SMALL MOLECULE DESIGN The inhibition of HIV-1 entry as a therapeutic strategy has been recently validated by a clinical study that demonstrated that a compound, T20, which targets gp41 and blocks HIV-1 entry, is highly efficient at controlling viral replication in patients (93). This raised the hope that entry-blocking agents will be the next generation of anti-hiv drugs (94). Small molecules that bind to gp120 with high affinity and block crucial steps of viral entry would be desirable. The complex strategies that HIV has evolved to evade Abs may not be as efficient against small compounds. The resolution of the structure of gp120 might help the design of such agents. In particular the two conserved binding sites are potential targets for therapeutic intervention (95). However, as explained before, the unliganded gp120 molecule may adopt a different conformation than the CD4-liganded crystal structure that has been solved. The Phe43 cavity of the CD4 binding site might thus not be preserved in the absence of CD4 (22). The coreceptor binding site is an attractive target as it is very conserved, but its access is difficult because it is mostly hidden before CD4 ligation. However, in contrast to Abs, small compounds may be able to access the coreceptor binding site after CD4 binding despite steric constraints due to the proximity of the cell membrane. Molecules that mimic CD4 could trigger conformational changes and expose the coreceptor binding site, permitting the binding of small coreceptor binding inhibitors. Of note, the resolution of the crystal structure of a fragment of gp41 has permitted an elegant series of studies resulting in the identification of a pocket on gp41 as a potential drug target (55, 96). Small peptides have been designed that block this cavity and inhibit HIV-1 entry (97). CONCLUDING REMARKS Despite the hundreds of monoclonal Abs of rodent and human origin that have been generated against gp120, only two Abs that potently neutralize a broad range of primary isolates are available to date: the Abs b12 and 2G12. This illustrates the

15 HIV-1 GP120 STRUCTURE AND FUNCTION 267 success of the strategies evolved by HIV to avoid Ab inactivation. Recent progress in the knowledge of HIV envelope glycoprotein structure further elucidates some of the viral strategies of Ab evasion. Although the targets of neutralizing Abs are now better understood, we still do not have immunogens that will elicit these Abs at useful levels. This remains a major challenge for vaccine design. The success of the T20 peptide, which targets gp41, will certainly intensify the search for small molecules that interfere with the viral entry process. This class of drug will, one hopes, be in common use in future years. The search for such small molecules and for improved immunogens would benefit from increased structural knowledge of gp120, especially from a crystal structure of an unliganded gp120 and of the gp120-gp41 trimeric complex. ACKNOWLEDGMENTS We thank J Sodroski and Z Huang for gp120 and CCR5 coordinates, respectively. We are grateful to J Sodroski and R Wyatt for critical review of the manuscript. EOS wishes to acknowledge Ian A Wilson for generous support. This work was supported by grants from the National Institute of Health AI45357(to PP), AI40377 (to PWHI), GM (to IAW), AI33292 and HL59727 (to DRB). Visit the Annual Reviews home page at LITERATURE CITED 1. Parren PWHI, Moore JP, Burton DR, Sattentau QJ The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity. Aids 13:S Parren PWHI, Burton DR The antiviral activity of antibodies in vitro and in vivo. Adv. Immunol. In press 3. Sattentau QJ, Moulard M, Brivet B, Botto F, Guillemot JC, Mondor I, Poignard P, Ugolini S Antibody neutralization of HIV-1 and the potential for vaccine design. Immunol. Lett. 66: Berger EA, Murphy PM, Farber JM Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17: Alkhatib G, Combadiere C, Broder C, Feng Y, Kennedy P, Murphy P, Berger E CC CKR5: a RANTES, MIP- 1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272: Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton R, Hill C, Davis C, Peiper S, Schall T, Littman D, Landau N Identification of a major co-receptor for primary isolates of HIV-1. Nature 381: Doranz B, Rucker J, Yi Y, Smyth R, Samson M, Peiper S, Parmentier M, Collman R, Doms R A dual-tropic primary HIV-1 isolate that uses fusin and the betachemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85: Dragic T, Litwin V, Allaway G, Martin S, Huang Y, Nagashima K, Cayanan C, Maddon P, Koup R, Moore JP, Paxton W HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381: Feng Y, Broder CC, Kennedy PE, Berger EA HIV-1 entry cofactor: functional cdna cloning of a seven-transmembrane,

16 268 POIGNARD ET AL G protein-coupled receptor. Science 272: Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiplyexposed individuals to HIV-1 infection. Cell 86: Samson M, Libert F, Doranz B, Rucker J, Liesnard C, Farber C, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth R, Collman R, Doms R, Vassart G, Parmentier M Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: Connor R, Sheridan K, Ceradini D, Choe S, Landau N Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J. Exp. Med. 185: Dean M, Carrington M, Winkler C, Huttley G, Smith M, Allikmets R, Goedert J, Buchbinder S, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O Brien S Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273: Smith M, Dean M, Carrington M, Winkler C, Huttley G, Lomb D, Goedert J, O Brien T, Jacobson L, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner M, O Brien S Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science 277: Zimmerman P, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C, Weissman D, Cohen O, Rubbert A, Lam G, Vaccarezza M, Kennedy P, Kumaraswami V, Giorgi J, Detels R, Hunter J, Chopek M, Berger E, Fauci A, Nutman T, Murphy P Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol. Med. 3: Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, Birx DL, Sheppard HW The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat. Med. 3: Lu M, Blacklow SC, Kim PS A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat. Struct. Biol. 2: Kowalski M, Potz J, Basiripour L, Dorfman T, Goh WC, Terwilliger E, Dayton A, Rosen C, Haseltine W, Sodroski J Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 237: Leonard CK, Spellman NW, Riddle L, Harris RJ, Thomas JN, Gregory TJ Assignment of intrachain disulphide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J. Biol. Chem. 265: Starlich BR, Hahn BH, Shaw GM, Mc- Neely PD, Modrow S, Wolf H, Parks ES, Parks WP, Josephs SF, Gallo RC Identification and characterisation of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 45:637 48

17 HIV-1 GP120 STRUCTURE AND FUNCTION Burton DR, Montefiori D The antibody response in HIV-1 infection. AIDS 11(Suppl A):S87 S Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393: Wyatt R, Sodroski J The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280: Wyatt R, Kwong PD, Desjardins E, Sweet RW, Robinson J, Hendrickson WA, Sodroski JG The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393: Binley JM, Wyatt R, Desjardins E, Kwong PD, Hendrickson W, Moore JP, Sodroski J Analysis of the interaction of antibodies with a conserved enzymatically deglycosylated core of the HIV type 1 envelope glycoprotein 120. AIDS Res. Hum. Retroviruses 14: Rizzuto CD, Wyatt R, Hernandez-Ramos N, Sun Y, Kwong PD, Hendrickson WA, Sodroski J A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280: Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384: Farzan M, Choe H, Vaca L, Martin K, Sun Y, Desjardins E, Ruffing N, Wu L, Wyatt R, Gerard N, Gerard C, Sodroski J A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J. Virol. 72: Dragic T, Trkola A, Lin SW, Nagashima KA, Kajumo F, Zhao L, Olson WC, Wu L, Mackay CR, Allaway GP, Sakmar TP, Moore JP, Maddon PJ Aminoterminal substitutions in the CCR5 coreceptor impair gp120 binding and human immunodeficiency virus type 1 entry. J. Virol. 72: Rabut GE, Konner JA, Kajumo F, Moore JP, Dragic T Alanine substitutions of polar and nonpolar residues in the aminoterminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. J. Virol. 72: Kwong PD, Wyatt R, Sattentau QJ, Sodroski J, Hendrickson WA Oligomeric modeling and electrostatic analysis of the gp120 envelope glycoprotein of human immunodeficiency virus. J. Virol. 74: Wyatt R, Moore JP, Accola M, Desjardin E, Robinson J, Sodroski J Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. J. Virol. 69: Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath P, Wu L, Mackay C, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85: Hoffman TL, LaBranche CC, Zhang W, Canziani G, Robinson J, Chaiken I, Hoxie JA, Doms RW Stable exposure of the coreceptor-binding site in a CD4- independent HIV- 1 envelope protein. Proc. Natl. Acad. Sci. USA 96: Hesselgesser J, Halks-Miller M, DelVecchio V, Peiper SC, Hoxie J, Kolson DL, Taub D, Horuk R CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Curr. Biol. 7: Bandres JC, Wang QF, O Leary J, Baleaux F, Amara A, Hoxie JA, Zolla-Pazner S,

18 270 POIGNARD ET AL Gorny MK Human immunodeficiency virus (HIV) envelope binds to CXCR4 independently of CD4, and binding can be enhanced by interaction with soluble CD4 or by HIV envelope deglycosylation. J. Virol. 72: Dumonceaux J, Nisole S, Chanel C, Quivet L, Amara A, Baleux F, Briand P, Hazan U Spontaneous mutations in the env gene of the human immunodeficiency virus type 1 NDK isolate are associated with a CD4-independent entry phenotype. J. Virol. 72: Bieniasz PD, Cullen BR Chemokine receptors and human immunodeficiency virus infection. Front. Biosci. 3:D Mondor I, Ugolini S, Sattentau QJ Human immunodeficiency virus type 1 attachment to HeLa CD4 cells is CD4 independent and gp120 dependent and requires cell surface heparans. J. Virol. 72: Moulard M, Lortat-Jacob H, Mondor I, Roca G, Wyatt R, Sodroski J, Zhao L, Olson W, Kwong PD, Sattentau QJ Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120. J. Virol. 74: Curtis BM, Scharnowske S, Watson AJ Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA 89: Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, Figdor CG Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100: Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG, van Kooyk Y DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100: Chan DC, Kim PS HIV entry and its inhibition. Cell 93: Gelderblom HR, Hausmann EH, Ozel M, Pauli G, Koch MA Fine structure of human immunodeficiency virus (HIV) and immunolocalization of structural proteins. Virology 156: Ozel M, Pauli G, Gelderblom HR The organization of the envelope projections on the surface of HIV. Arch. Virol. 100: Nermut MV, Grief C, Hashmi S, Hockley DJ Further evidence of icosahedral symmetry in human and simian immunodeficiency virus. AIDS Res. Hum. Retroviruses 9: Rao Z, Belyaev AS, Fry E, Roy P, Jones IM, Stuart DI Crystal structure of SIV matrix antigen and implications for virus assembly. Nature 378: Nermut MV, Hockley DJ, Bron P, Thomas D, Zhang WH, Jones IM Further evidence for hexagonal organization of HIV gag protein in prebudding assemblies and immature virus-like particles. J. Struct. Biol. 123: Nermut MV, Hockley DJ, Jowett JB, Jones IM, Garreau M, Thomas D Fullerene-like organization of HIV gagprotein shell in virus-like particles produced by recombinant baculovirus. Virology 198: Forster MJ, Mulloy B, Nermut MV Molecular modelling study of HIV p17gag (MA) protein shell utilising data from electron microscopy and X-ray crystallography. J. Mol. Biol. 298: Sattentau QJ, Moore JP Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J. Exp. Med. 174: Sattentau QJ, Moore JP, Vignaux F, Traincard F, Poignard P Conformational changes induced in the envelope

19 HIV-1 GP120 STRUCTURE AND FUNCTION 271 glycoproteins of the human and simian immunodeficiency viruses by soluble receptor binding. J. Virol. 67: Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC Atomic structure of the ectodomain from HIV-1 gp41. Nature 387: Chan DC, Fass D, Berger JM, Kim PS Core structure of gp41 from the HIV envelope glycoprotein. Cell 89: Jones PL, Korte T, Blumenthal R Conformational changes in cell surface HIV-1 envelope glycoproteins are triggered by cooperation between cell surface CD4 and co-receptors. J. Biol. Chem. 273: Burton DR A vaccine for HIV type 1: the antibody perspective. Proc. Natl. Acad. Sci. USA 94: Moore JP, Sattentau QJ, Wyatt R, Sodroski J Probing the structure of the human immunodeficiency virus surface glycoprotein gp120 with a panel of monoclonal antibodies. J. Virol. 68: Moore JP, Sodroski J Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein. J. Virol. 70: Sattentau QJ, Moore JP Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer. J. Exp. Med. 182: Alexander S, Elder JH Carbohydrate dramatically influences immune reactivity of antisera to viral glycoprotein antigens. Science 226: Stamatatos L, Zolla-Pazner S, Gorny MK, Cheng-Mayer C Binding of antibodies to virion-associated gp120 molecules of primary-like human immunodeficiency virus type 1 (HIV-1) isolates: effect on HIV-1 infection of macrophages and peripheral blood mononuclear cells. Virology 229: Fouts TR, Trkola A, Fung MS, Moore JP Interactions of polyclonal and monoclonal anti-glycoprotein 120 antibodies with oligomeric glycoprotein 120- glycoprotein 41 complexes of a primary HIV type 1 isolate: relationship to neutralization. AIDS Res. Hum. Retroviruses 14: Nyambi PN, Gorny MK, Bastiani L, van der Groen G, Williams C, Zolla-Pazner S Mapping of epitopes exposed on intact human immunodeficiency virus type 1 (HIV-1) virions: a new strategy for studying the immunologic relatedness of HIV-1. J. Virol. 72: Nyambi PN, Mbah HA, Burda S, Williams C, Gorny MK, Nadas A, Zolla-Pazner S Conserved and exposed epitopes on intact, native, primary human immunodeficiency virus type 1 virions of group M. J. Virol. 74: Parren PWHI, Burton DR, Sattentau QJ HIV-1 antibody debris or virion? Nat. Med. 3: Bachmann MF, Zinkernagel RM Neutralizing antiviral B cell responses. Annu. Rev. Immunol. 15: Poignard P, Klasse PJ, Sattentau QJ Antibody neutralization of HIV-1. Immunol. Today 17: Moore JP, Cao Y, Qing L, Sattentau QJ, Pyati J, Koduri R, Robinson J, Barbas CF 3rd, Burton DR, Ho DD Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120. J. Virol. 69: Fouts TR, Binley JM, Trkola A, Robinson JE, Moore JP Neutralization of the human immunodeficiency virus type 1 primary isolate JR-FL by human monoclonal antibodies correlates with antibody binding to the oligomeric form of the envelope glycoprotein complex. J. Virol. 71: Bou-Habib DC, Roderiquez G, Oravecz T, Berman PW, Lusso P, Norcross MA

20 272 POIGNARD ET AL Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization. J. Virol. 68: D Souza MP, Livnat D, Bradac JA, Bridges SH Evaluation of monoclonal antibodies to human immunodeficiency virus type 1 primary isolates by neutralization assays: performance criteria for selecting candidate antibodies for clinical trials. AIDS Clinical Trials Group Antibody Selection Working Group. J. Infect. Dis. 175: Burton DR, Barbas CF 3d, Persson M, Koenig S, Chanock R, Lerner R A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Natl. Acad. Sci. USA 88: Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PWHI, Sawyer LS, Hendry RM, Dunlop N, Nara PL, et al Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266: Roben P, Moore JP, Thali M, Sodroski J, Barbas CF 3rd, Burton DR Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J. Virol. 68: Trkola A, Purtscher M, Muster T, Ballaun C, Buchacher A, Sullivan N, Srinivasan K, Sodroski J, Moore JP, Katinger H Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70: Thali M, Furman C, Ho DD, Robinson J, Tilley S, Pinter A, Sodroski J Discontinuous, conserved neutralization epitopes overlapping the CD4-binding region of human immunodeficiency virus type 1 gp120 envelope glycoprotein. J. Virol. 66: Thali M, Moore JP, Furman C, Charles M, Ho DD, Robinson J, Sodroski J Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120- CD4 binding. J. Virol. 67: Trkola A, Pomales AB, Yuan H, Korber B, Maddon PJ, Allaway GP, Katinger H, Barbas CF 3rd, Burton DR, Ho DD, et al Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J. Virol. 69: Trkola A, Dragic T, Arthos J, Binley JM, Olson WC, Allaway GP, Cheng-Mayer C, Robinson J, Maddon PJ, Moore JP CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384: Stanfield R, Cabezas E, Satterthwait A, Stura E, Profy A, Wilson I Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing fabs. Structure Fold. Des. 7: Pinter A, Honnen WJ, Kayman SC, Trochev O, Wu Z Potent neutralization of primary HIV-1 isolates by antibodies directed against epitopes present in the V1/V2 domain of HIV-1 gp120. Vaccine 16: Parren PWHI, Mondor I, Naniche D, Ditzel HJ, Klasse PJ, Burton DR, Sattentau QJ Neutralization of human immunodeficiency virus type 1 by antibody to gp120 is determined primarily by occupancy of sites on the virion irrespective of epitope specificity. J. Virol. 72: Ugolini S, Mondor I, Parren PWHI, Burton DR, Tilley SA, Klasse PJ, Sattentau QJ Inhibition of virus attachment to CD4+ target cells is a major mechanism of T cell line-adapted HIV-1 neutralization. J. Exp. Med. 186:

21 HIV-1 GP120 STRUCTURE AND FUNCTION Valenzuela A, Blanco J, Krust B, Franco R, Hovanessian AG Neutralizing antibodies against the V3 loop of human immunodeficiency virus type 1 gp120 block the CD4-dependent and -independent binding of virus to cells. J. Virol. 71: Schönning K, Lund O, Lund OS, Hansen JE Stoichiometry of monoclonal antibody neutralization of T-cell line-adapted human immunodeficiency virus type 1. J. Virol. 73: Rossio JL, Esser MT, Suryanarayana K, Schneider DK, Bess JW Jr, Vasquez GM, Wiltrout TA, Chertova E, Grimes MK, Sattentau Q, Arthur LO, Henderson LE, Lifson JD Inactivation of human immunodeficiency virus type 1 infectivity with preservation of conformational and functional integrity of virion surface proteins. J. Virol. 72: Yang X, Florin L, Farzan M, Kolchinsky P, Kwong PD, Sodroski J, Wyatt R Modifications that stabilize human immunodeficiency virus envelope glycoprotein trimers in solution. J. Virol. 74: Yang X, Farzan M, Wyatt R, Sodroski J Characterization of stable, soluble trimers containing complete ectodomains of human immunodeficiency virus type 1 envelope glycoproteins. J. Virol. 74: Binley JM, Sanders RW, Clas B, Schuelke N, Master A, Guo Y, Kajumo F, Anselma DJ, Maddon PJ, Olson WC, Moore JP A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J. Virol. 74: Reitter JN, Means RE, Desrosiers RC A role for carbohydrates in immune evasion in AIDS. Nat. Med. 4: Burton DR, Parren PWHI Vaccines and the induction of functional antibodies: time to look beyond the molecules of natural infection? Nat. Med. 6: Kilby JM, Hopkins S, Venetta TM, Di- Massimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, Matthews T, Johnson MR, Nowak MA, Shaw GM, Saag MS Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat. Med. 4: Blair WS, Lin PF, Meanwell NA, Wallace OB HIV-1 entry an expanding portal for drug discovery. Drug Discov. Today. 5: Vita C, Drakopoulou E, Vizzavona J, Rochette S, Martin L, Menez A, Roumestand C, Yang YS, Ylisastigui L, Benjouad A, Gluckman JC Rational engineering of a miniprotein that reproduces the core of the CD4 site interacting with HIV-1 envelope glycoprotein. Proc. Natl. Acad. Sci. USA 96: Chan DC, Chutkowski CT, Kim PS Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proc. Natl. Acad. Sci. USA 95: Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 99: Sanner MF, Olson AJ, Spehner JC Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 38: Sanner MF Python: a programming language for software integration and development. J. Mol. Graph. Model. 17: Wormald MR, Wooten EW, Bazzo R, Edge CJ, Feinstein A, Rademacher TW, Dwek RA The conformational effects of N-glycosylation on the tailpiece from serum IgM. Eur. J. Biochem. 198:131 39

22 274 POIGNARD ET AL 101. Imberty A, Perez S Stereochemistry of the N-glycosylation sites in glycoproteins. Protein Eng. 8: Jones TA Diffraction methods for biological macromolecules. Interactive computer graphics: FRODO. Methods Enzymol. 115: Wu H, Kwong PD, Hendrickson WA Dimeric association and segmental variability in the structure of human CD4. Nature 387: Zhou N, Luo Z, Hall JW, Luo J, Han X, Huang Z Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction. Eur. J. Immunol. 30: Gauduin MC, Parren PW, Weir R, Barbas CF, Burton DR, Koup RA Passive immunization with a human monoclonal antibody protects hu-pbl-scid mice against challenge by primary isolates of HIV-1. Nat. Med. 3: Shibata R, Igarashi T, Haigwood N, Buckler-White A, Ogert R, Ross W, Willey R, Cho MW, Martin MA Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat. Med. 5: Baba TW, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, Cavacini LA, Posner MR, Katinger H, Stiegler G, Bernacky BJ, Rizvi TA, Schmidt R, Hill LR, Keeling ME, Lu Y, Wright JE, Chou TC, Ruprecht RM Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simianhuman immunodeficiency virus infection. Nat. Med. 6: Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, Beary H, Hayes D, Frankel SS, Birx DL, Lewis MG Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6:207 10

23 Figure 1 The structure of the gp120 core. Top panel: The CD4-gp120 interface is shown in yellow. Proposed crucial residues for the binding of CD4 and CCR5 are highlighted in orange and blue, respectively. Middle panel: Proposed crucial residues for the binding of monoclonal Abs b12 and 2G12 are highlighted in red and green, respectively. Bottom panel: The faces of the gp120 core. The neutralizing face of primary viruses is highlighted in yellow. The neutralizing face of TCLA viruses corresponds to the grey and yellow surface. Gp120 surfaces were generated using coordinates from Kwong et al. (22). Graphics were produced using MSMS (98) and visualized in PMV (99). Modeling of carbohydrates was based on preferred structures and torsion angles as in (100, 101) and done using TOM/FRODO (102).

24 Figure 2 Schematic model of HIV-1 entry. a) The first step of HIV-1 entry is the binding of the gp120 surface molecule to its receptor, the CD4 molecule, at the surface of the target cell. b) Ligation of CD4 to gp120 leads to conformational changes in the envelope complex that permit exposure of the coreceptor binding site. c) The gp41 fusion peptide inserts into the target cell membrane leading to the formation of the prehairpin intermediate. d) The formation of the coiled-coil leads to membrane fusion and to the penetration of HIV-1 genetic information into the target cell.

25 Figure 3 Model of neutralization of HIV-1 by Abs. The Ab b12 binds to envelope spikes on the viral membrane (top) and prevents interaction with cell membrane viral receptors (bottom). Envelope trimer assembly was done as in (31) using TOM /FRODO (102), and carbohydrates were added. Coordinates for gp120, gp41, CD4 and CCR5 are from (22), (54), (103) and (104), respectively. Coordinates for b12 are from E. Ollman Saphire et al. (manuscript in preparation).

EMERGING ISSUES IN THE HUMORAL IMMUNE RESPONSE TO HIV. (Summary of the recommendations from an Enterprise Working Group)

EMERGING ISSUES IN THE HUMORAL IMMUNE RESPONSE TO HIV. (Summary of the recommendations from an Enterprise Working Group) AIDS Vaccine 07, Seattle, August 20-23, 2007 EMERGING ISSUES IN THE HUMORAL IMMUNE RESPONSE TO HIV (Summary of the recommendations from an Enterprise Working Group) The Working Group Reston, Virginia,

More information

Crystal structure of the neutralizing antibody HK20 in complex with its gp41 antigen

Crystal structure of the neutralizing antibody HK20 in complex with its gp41 antigen Crystal structure of the neutralizing antibody HK20 in complex with its gp41 antigen David Lutje Hulsik Unit for Virus Host Cell Interaction UMI 3265 University Joseph Fourier-EMBL-CNRS, Grenoble Env catalyzed

More information

Received October 3, 1997; accepted February 10, 1998

Received October 3, 1997; accepted February 10, 1998 VIROLOGY 244, 66 73 (1998) ARTICLE NO. VY989082 Reduced HIV-1 Infectability of CD4 Lymphocytes from Exposed-Uninfected Individuals: Association with Low Expression of CCR5 and High Production of -Chemokines

More information

HIV Anti-HIV Neutralizing Antibodies

HIV Anti-HIV Neutralizing Antibodies ,**/ The Japanese Society for AIDS Research The Journal of AIDS Research : HIV HIV Anti-HIV Neutralizing Antibodies * Junji SHIBATA and Shuzo MATSUSHITA * Division of Clinical Retrovirology and Infectious

More information

Identification of Mutation(s) in. Associated with Neutralization Resistance. Miah Blomquist

Identification of Mutation(s) in. Associated with Neutralization Resistance. Miah Blomquist Identification of Mutation(s) in the HIV 1 gp41 Subunit Associated with Neutralization Resistance Miah Blomquist What is HIV 1? HIV-1 is an epidemic that affects over 34 million people worldwide. HIV-1

More information

Antigen Receptor Structures October 14, Ram Savan

Antigen Receptor Structures October 14, Ram Savan Antigen Receptor Structures October 14, 2016 Ram Savan savanram@uw.edu 441 Lecture #8 Slide 1 of 28 Three lectures on antigen receptors Part 1 (Today): Structural features of the BCR and TCR Janeway Chapter

More information

2005 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.

2005 LANDES BIOSCIENCE. DO NOT DISTRIBUTE. [Human Vaccines 1:2, 45-60; March/April 2005]; 2005 Landes Bioscience Review Role of Neutralizing Antibodies in Protective Immunity Against HIV Indresh K. Srivastava* Jeffrey B. Ulmer Susan W. Barnett

More information

From Antibody to Vaccine a Tale of Structural Biology and Epitope Scaffolds

From Antibody to Vaccine a Tale of Structural Biology and Epitope Scaffolds Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services From Antibody to Vaccine a Tale

More information

YUMI YAMAGUCHI-KABATA AND TAKASHI GOJOBORI* Center for Information Biology, National Institute of Genetics, Mishima , Japan

YUMI YAMAGUCHI-KABATA AND TAKASHI GOJOBORI* Center for Information Biology, National Institute of Genetics, Mishima , Japan JOURNAL OF VIROLOGY, May 2000, p. 4335 4350 Vol. 74, No. 9 0022-538X/00/$04.00 0 Copyright 2000, American Society for Microbiology. All Rights Reserved. Reevaluation of Amino Acid Variability of the Human

More information

Challenges in Designing HIV Env Immunogens for Developing a Vaccine

Challenges in Designing HIV Env Immunogens for Developing a Vaccine b514_chapter-13.qxd 12/4/2007 3:39 PM Page 327 Chapter 13 Challenges in Designing HIV Env Immunogens for Developing a Vaccine Indresh K. Srivastava* and R. Holland Cheng Summary HIV continues to be a major

More information

Rama Abbady. Odai Bani-Monia. Diala Abu-Hassan

Rama Abbady. Odai Bani-Monia. Diala Abu-Hassan 5 Rama Abbady Odai Bani-Monia Diala Abu-Hassan Lipid Rafts Lipid rafts are aggregates (accumulations) of sphingolipids. They re semisolid clusters (10-200 nm) of cholesterol and sphingolipids (sphingomyelin

More information

Third line of Defense

Third line of Defense Chapter 15 Specific Immunity and Immunization Topics -3 rd of Defense - B cells - T cells - Specific Immunities Third line of Defense Specific immunity is a complex interaction of immune cells (leukocytes)

More information

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES 1 of 7 I. Viral Origin. A. Retrovirus - animal lentiviruses. HIV - BASIC PROPERTIES 1. HIV is a member of the Retrovirus family and more specifically it is a member of the Lentivirus genus of this family.

More information

The challenge of an HIV vaccine from the antibody perspective. Dennis Burton The Scripps Research Institute

The challenge of an HIV vaccine from the antibody perspective. Dennis Burton The Scripps Research Institute The challenge of an HIV vaccine from the antibody perspective Dennis Burton The Scripps Research Institute AIDS Pandemic Nov 2005 North America 1.2 million [650 000 1.8 million] Caribbean 300 000 [200

More information

Structural Insights into HIV-1 Neutralization by Broadly Neutralizing Antibodies PG9 and PG16

Structural Insights into HIV-1 Neutralization by Broadly Neutralizing Antibodies PG9 and PG16 Structural Insights into HIV-1 Neutralization by Broadly Neutralizing Antibodies PG9 and PG16 Robert Pejchal, Laura M. Walker, Robyn L. Stanfield, Wayne C. Koff, Sanjay K. Phogat, Pascal Poignard, Dennis

More information

ARV Mode of Action. Mode of Action. Mode of Action NRTI. Immunopaedia.org.za

ARV Mode of Action. Mode of Action. Mode of Action NRTI. Immunopaedia.org.za ARV Mode of Action Mode of Action Mode of Action - NRTI Mode of Action - NNRTI Mode of Action - Protease Inhibitors Mode of Action - Integrase inhibitor Mode of Action - Entry Inhibitors Mode of Action

More information

Adaptive Immunity: Humoral Immune Responses

Adaptive Immunity: Humoral Immune Responses MICR2209 Adaptive Immunity: Humoral Immune Responses Dr Allison Imrie 1 Synopsis: In this lecture we will review the different mechanisms which constitute the humoral immune response, and examine the antibody

More information

Glycosylation of the ENV Spike of Primate Immunodeficiency Viruses and Antibody Neutralization

Glycosylation of the ENV Spike of Primate Immunodeficiency Viruses and Antibody Neutralization Current HIV Research, 2004, 2, 243-254 243 Glycosylation of the ENV Spike of Primate Immunodeficiency Viruses and Antibody Neutralization Cheryl A. Pikora *1,2 1 Department of Infectious Diseases, Children

More information

Polyomaviridae. Spring

Polyomaviridae. Spring Polyomaviridae Spring 2002 331 Antibody Prevalence for BK & JC Viruses Spring 2002 332 Polyoma Viruses General characteristics Papovaviridae: PA - papilloma; PO - polyoma; VA - vacuolating agent a. 45nm

More information

HUMAN IMMUNODEFICIENCY VIRUS

HUMAN IMMUNODEFICIENCY VIRUS Futuro promisorio de la terapia antirretroviral: Nuevos blancos terapéuticos. María José Míguez, M.D., PhD., Universidad de Miami, EE.UU. HUMAN IMMUNODEFICIENCY VIRUS REVERSE TRANSCRIPTASA REPLICATION

More information

TEMA 5. ANTICUERPOS Y SUS RECEPTORES

TEMA 5. ANTICUERPOS Y SUS RECEPTORES TEMA 5. ANTICUERPOS Y SUS RECEPTORES The B-cell antigen receptor (left) consists of two identical heavy (H) chains and two identical light (L) chains. In addition, secondary components (Ig-α and Ig-β)

More information

CD4 T Cell Decline Is Not Associated With Amino Acid Changes in HIV-1 gp120

CD4 T Cell Decline Is Not Associated With Amino Acid Changes in HIV-1 gp120 CD4 T Cell Decline Is Not Associated With Amino Acid Changes in HIV-1 gp120 Colin Wikholm and Isai Lopez BIOL 368: Bioinformatics Laboratory Department of Biology Loyola Marymount University November 15,

More information

MECHANISMS OF VIRAL MEMBRANE FUSION AND ITS INHIBITION

MECHANISMS OF VIRAL MEMBRANE FUSION AND ITS INHIBITION Annu. Rev. Biochem. 2001. 70:777 810 Copyright c 2001 by Annual Reviews. All rights reserved MECHANISMS OF VIRAL MEMBRANE FUSION AND ITS INHIBITION DebraM.EckertandPeterS.Kim 1 Howard Hughes Medical Institute,

More information

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody CD4 binding induces conformational changes in the gp120 glycoprotein, some of which involve the exposure and/or formation of a binding site for specific chemokine receptors. These chemokine receptors,

More information

MedChem 401~ Retroviridae. Retroviridae

MedChem 401~ Retroviridae. Retroviridae MedChem 401~ Retroviridae Retroviruses plus-sense RNA genome (!8-10 kb) protein capsid lipid envelop envelope glycoproteins reverse transcriptase enzyme integrase enzyme protease enzyme Retroviridae The

More information

STRUCTURE, GENERAL CHARACTERISTICS AND REPRODUCTION OF VIRUSES

STRUCTURE, GENERAL CHARACTERISTICS AND REPRODUCTION OF VIRUSES STRUCTURE, GENERAL CHARACTERISTICS AND REPRODUCTION OF VIRUSES Introduction Viruses are noncellular genetic elements that use a living cell for their replication and have an extracellular state. Viruses

More information

RAISON D ETRE OF THE IMMUNE SYSTEM:

RAISON D ETRE OF THE IMMUNE SYSTEM: RAISON D ETRE OF THE IMMUNE SYSTEM: To Distinguish Self from Non-Self Thereby Protecting Us From Our Hostile Environment. Innate Immunity Acquired Immunity Innate immunity: (Antigen nonspecific) defense

More information

Immunology - Lecture 2 Adaptive Immune System 1

Immunology - Lecture 2 Adaptive Immune System 1 Immunology - Lecture 2 Adaptive Immune System 1 Book chapters: Molecules of the Adaptive Immunity 6 Adaptive Cells and Organs 7 Generation of Immune Diversity Lymphocyte Antigen Receptors - 8 CD markers

More information

Lecture 15. Membrane Proteins I

Lecture 15. Membrane Proteins I Lecture 15 Membrane Proteins I Introduction What are membrane proteins and where do they exist? Proteins consist of three main classes which are classified as globular, fibrous and membrane proteins. A

More information

Antigen Recognition by T cells

Antigen Recognition by T cells Antigen Recognition by T cells TCR only recognize foreign Ags displayed on cell surface These Ags can derive from pathogens, which replicate within cells or from pathogens or their products that cells

More information

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Medical Virology Immunology Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Human blood cells Phases of immune responses Microbe Naïve

More information

Third line of Defense. Topic 8 Specific Immunity (adaptive) (18) 3 rd Line = Prophylaxis via Immunization!

Third line of Defense. Topic 8 Specific Immunity (adaptive) (18) 3 rd Line = Prophylaxis via Immunization! Topic 8 Specific Immunity (adaptive) (18) Topics - 3 rd Line of Defense - B cells - T cells - Specific Immunities 1 3 rd Line = Prophylaxis via Immunization! (a) A painting of Edward Jenner depicts a cow

More information

HIV Immunopathogenesis. Modeling the Immune System May 2, 2007

HIV Immunopathogenesis. Modeling the Immune System May 2, 2007 HIV Immunopathogenesis Modeling the Immune System May 2, 2007 Question 1 : Explain how HIV infects the host Zafer Iscan Yuanjian Wang Zufferey Abhishek Garg How does HIV infect the host? HIV infection

More information

Citation for published version (APA): Von Eije, K. J. (2009). RNAi based gene therapy for HIV-1, from bench to bedside

Citation for published version (APA): Von Eije, K. J. (2009). RNAi based gene therapy for HIV-1, from bench to bedside UvA-DARE (Digital Academic Repository) RNAi based gene therapy for HIV-1, from bench to bedside Von Eije, K.J. Link to publication Citation for published version (APA): Von Eije, K. J. (2009). RNAi based

More information

CCR5 genotype and plasma ß-chemokine concentration of Brazilian HIV-infected individuals

CCR5 genotype and plasma ß-chemokine concentration of Brazilian HIV-infected individuals Brazilian Journal of Medical and Biological Research (2002) 35: 1333-1337 The 32ccr5 allele and plasma ß-chemokine concentration ISSN 0100-879X Short Communication 1333 CCR5 genotype and plasma ß-chemokine

More information

Structural biology of viruses

Structural biology of viruses Structural biology of viruses Biophysical Chemistry 1, Fall 2010 Coat proteins DNA/RNA packaging Reading assignment: Chap. 15 Virus particles self-assemble from coat monomers Virus Structure and Function

More information

Levels of Protein Structure:

Levels of Protein Structure: Levels of Protein Structure: PRIMARY STRUCTURE (1 ) - Defined, non-random sequence of amino acids along the peptide backbone o Described in two ways: Amino acid composition Amino acid sequence M-L-D-G-C-G

More information

Supporting Information

Supporting Information Supporting Information Guan et al. 10.1073/pnas.1217609110 Fig. S1. Three patterns of reactivity for CD4-induced (CD4i) mabs. The following representative ELISAs show three patterns of reactivity for CD4i

More information

RAISON D ETRE OF THE IMMUNE SYSTEM:

RAISON D ETRE OF THE IMMUNE SYSTEM: RAISON D ETRE OF THE IMMUNE SYSTEM: To Distinguish Self from Non-Self Thereby Protecting Us From Our Hostile Environment. Innate Immunity Adaptive Immunity Innate immunity: (Antigen - nonspecific) defense

More information

Protein Trafficking in the Secretory and Endocytic Pathways

Protein Trafficking in the Secretory and Endocytic Pathways Protein Trafficking in the Secretory and Endocytic Pathways The compartmentalization of eukaryotic cells has considerable functional advantages for the cell, but requires elaborate mechanisms to ensure

More information

Chapter 6. Antigen Presentation to T lymphocytes

Chapter 6. Antigen Presentation to T lymphocytes Chapter 6 Antigen Presentation to T lymphocytes Generation of T-cell Receptor Ligands T cells only recognize Ags displayed on cell surfaces These Ags may be derived from pathogens that replicate within

More information

Protein Structure and Function

Protein Structure and Function Protein Structure and Function Protein Structure Classification of Proteins Based on Components Simple proteins - Proteins containing only polypeptides Conjugated proteins - Proteins containing nonpolypeptide

More information

Translation. Host Cell Shutoff 1) Initiation of eukaryotic translation involves many initiation factors

Translation. Host Cell Shutoff 1) Initiation of eukaryotic translation involves many initiation factors Translation Questions? 1) How does poliovirus shutoff eukaryotic translation? 2) If eukaryotic messages are not translated how can poliovirus get its message translated? Host Cell Shutoff 1) Initiation

More information

Catalysis & specificity: Proteins at work

Catalysis & specificity: Proteins at work Catalysis & specificity: Proteins at work Introduction Having spent some time looking at the elements of structure of proteins and DNA, as well as their ability to form intermolecular interactions, it

More information

Protein Modeling Event

Protein Modeling Event Protein Modeling Event School Name: School Number: Team Member 1: Team Member 2: : Pre-Build Score: On-Site Build Score: Test Score: Tie Breaker: Total: Final Rank: Part I: Pre-Build (40% of total score)

More information

The Adaptive Immune Response. T-cells

The Adaptive Immune Response. T-cells The Adaptive Immune Response T-cells T Lymphocytes T lymphocytes develop from precursors in the thymus. Mature T cells are found in the blood, where they constitute 60% to 70% of lymphocytes, and in T-cell

More information

There are approximately 30,000 proteasomes in a typical human cell Each proteasome is approximately 700 kda in size The proteasome is made up of 3

There are approximately 30,000 proteasomes in a typical human cell Each proteasome is approximately 700 kda in size The proteasome is made up of 3 Proteasomes Proteasomes Proteasomes are responsible for degrading proteins that have been damaged, assembled improperly, or that are of no profitable use to the cell. The unwanted protein is literally

More information

a) The statement is true for X = 400, but false for X = 300; b) The statement is true for X = 300, but false for X = 200;

a) The statement is true for X = 400, but false for X = 300; b) The statement is true for X = 300, but false for X = 200; 1. Consider the following statement. To produce one molecule of each possible kind of polypeptide chain, X amino acids in length, would require more atoms than exist in the universe. Given the size of

More information

HIV INFECTION: An Overview

HIV INFECTION: An Overview HIV INFECTION: An Overview UNIVERSITY OF PAPUA NEW GUINEA SCHOOL OF MEDICINE AND HEALTH SCIENCES DIVISION OF BASIC MEDICAL SCIENCES DISCIPLINE OF BIOCHEMISTRY & MOLECULAR BIOLOGY PBL MBBS II SEMINAR VJ

More information

PEPTIDE MARKERS FOR THE HIV-1 NEUTRALIZING ANTIBODY 4ElO. Sondra Lynne Bahr B. Sc., Simon Fraser University, 2000

PEPTIDE MARKERS FOR THE HIV-1 NEUTRALIZING ANTIBODY 4ElO. Sondra Lynne Bahr B. Sc., Simon Fraser University, 2000 PEPTIDE MARKERS FOR THE HIV-1 NEUTRALIZING ANTIBODY 4ElO Sondra Lynne Bahr B. Sc., Simon Fraser University, 2000 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF

More information

CS612 - Algorithms in Bioinformatics

CS612 - Algorithms in Bioinformatics Spring 2016 Protein Structure February 7, 2016 Introduction to Protein Structure A protein is a linear chain of organic molecular building blocks called amino acids. Introduction to Protein Structure Amine

More information

The recruitment of leukocytes and plasma proteins from the blood to sites of infection and tissue injury is called inflammation

The recruitment of leukocytes and plasma proteins from the blood to sites of infection and tissue injury is called inflammation The migration of a particular type of leukocyte into a restricted type of tissue, or a tissue with an ongoing infection or injury, is often called leukocyte homing, and the general process of leukocyte

More information

Cell Membranes. Dr. Diala Abu-Hassan School of Medicine Cell and Molecular Biology

Cell Membranes. Dr. Diala Abu-Hassan School of Medicine Cell and Molecular Biology Cell Membranes Dr. Diala Abu-Hassan School of Medicine Dr.abuhassand@gmail.com Cell and Molecular Biology Organelles 2Dr. Diala Abu-Hassan Membrane proteins Major components of cells Nucleic acids DNA

More information

H C. C α. Proteins perform a vast array of biological function including: Side chain

H C. C α. Proteins perform a vast array of biological function including: Side chain Topics The topics: basic concepts of molecular biology elements on Python overview of the field biological databases and database searching sequence alignments phylogenetic trees microarray data analysis

More information

P450 CYCLE. All P450s follow the same catalytic cycle of;

P450 CYCLE. All P450s follow the same catalytic cycle of; P450 CYCLE All P450s follow the same catalytic cycle of; 1. Initial substrate binding 2. First electron reduction 3. Oxygen binding 4. Second electron transfer 5 and 6. Proton transfer/dioxygen cleavage

More information

Macrophage Activation & Cytokine Release. Dendritic Cells & Antigen Presentation. Neutrophils & Innate Defense

Macrophage Activation & Cytokine Release. Dendritic Cells & Antigen Presentation. Neutrophils & Innate Defense Macrophage Activation & Cytokine Release Dendritic Cells & Antigen Presentation Neutrophils & Innate Defense Neutrophils Polymorphonuclear cells (PMNs) are recruited to the site of infection where they

More information

Mutants and HBV vaccination. Dr. Ulus Salih Akarca Ege University, Izmir, Turkey

Mutants and HBV vaccination. Dr. Ulus Salih Akarca Ege University, Izmir, Turkey Mutants and HBV vaccination Dr. Ulus Salih Akarca Ege University, Izmir, Turkey Geographic Distribution of Chronic HBV Infection 400 million people are carrier of HBV Leading cause of cirrhosis and HCC

More information

Spike Trimer RNA. dsdna

Spike Trimer RNA. dsdna Spike Trimer RNA dsdna Spike Trimer RNA Spike trimer subunits xxx gp120: receptor and coreceptor binding xxxxxxx gp41: membrane anchoring and target cell fusion dsdna Spike Trimer HIV gp120 binds to host

More information

Peptide hydrolysis uncatalyzed half-life = ~450 years HIV protease-catalyzed half-life = ~3 seconds

Peptide hydrolysis uncatalyzed half-life = ~450 years HIV protease-catalyzed half-life = ~3 seconds Uncatalyzed half-life Peptide hydrolysis uncatalyzed half-life = ~450 years IV protease-catalyzed half-life = ~3 seconds Life Sciences 1a Lecture Slides Set 9 Fall 2006-2007 Prof. David R. Liu In the absence

More information

Dr. Ahmed K. Ali Attachment and entry of viruses into cells

Dr. Ahmed K. Ali Attachment and entry of viruses into cells Lec. 6 Dr. Ahmed K. Ali Attachment and entry of viruses into cells The aim of a virus is to replicate itself, and in order to achieve this aim it needs to enter a host cell, make copies of itself and

More information

Severe Acute Respiratory Syndrome (SARS) Coronavirus

Severe Acute Respiratory Syndrome (SARS) Coronavirus Severe Acute Respiratory Syndrome (SARS) Coronavirus Coronaviruses Coronaviruses are single stranded enveloped RNA viruses that have a helical geometry. Coronaviruses are the largest of RNA viruses with

More information

CDC site UNAIDS Aids Knowledge Base http://www.cdc.gov/hiv/dhap.htm http://hivinsite.ucsf.edu/insite.jsp?page=kb National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/default.htm

More information

General information. Cell mediated immunity. 455 LSA, Tuesday 11 to noon. Anytime after class.

General information. Cell mediated immunity. 455 LSA, Tuesday 11 to noon. Anytime after class. General information Cell mediated immunity 455 LSA, Tuesday 11 to noon Anytime after class T-cell precursors Thymus Naive T-cells (CD8 or CD4) email: lcoscoy@berkeley.edu edu Use MCB150 as subject line

More information

Under the Radar Screen: How Bugs Trick Our Immune Defenses

Under the Radar Screen: How Bugs Trick Our Immune Defenses Under the Radar Screen: How Bugs Trick Our Immune Defenses Session 7: Cytokines Marie-Eve Paquet and Gijsbert Grotenbreg Whitehead Institute for Biomedical Research HHV-8 Discovered in the 1980 s at the

More information

Emerging Viruses. Part IIb Follow Up from Part I Vaccines and Inhibitors

Emerging Viruses. Part IIb Follow Up from Part I Vaccines and Inhibitors Emerging Viruses Part IIb Follow Up from Part I Vaccines and Inhibitors Cellular Responses to Viral Invasion: Restriction Factors Cells fight viral infection using a series of restriction factors Restriction

More information

Human Immunodeficiency Virus

Human Immunodeficiency Virus Human Immunodeficiency Virus Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics Viruses and hosts Lentivirus from Latin lentis (slow), for slow progression of disease

More information

Analysis of protein modeling for envelope glycoprotein GP120 for HIV via bioinformatics approaches

Analysis of protein modeling for envelope glycoprotein GP120 for HIV via bioinformatics approaches International Research Journal of Virology Vol. 1(1), pp. 002-006, March, 2014. www.premierpublishers.org ISSN: 2326-7193x IRJV Research Article Analysis of protein modeling for envelope glycoprotein GP120

More information

An aldose contains an aldehyde functionality A ketose contains a ketone functionality

An aldose contains an aldehyde functionality A ketose contains a ketone functionality RCT Chapter 7 Aldoses and Ketoses; Representative monosaccharides. (a)two trioses, an aldose and a ketose. The carbonyl group in each is shaded. An aldose contains an aldehyde functionality A ketose contains

More information

Critical Review. HIV Receptors and Cellular Tropism

Critical Review. HIV Receptors and Cellular Tropism IUBMB Life, 53: 201 205, 2002 Copyright c 2002 IUBMB 1521-6543/02 $12.00 +.00 DOI: 10.1080/15216540290098927 Critical Review HIV Receptors and Cellular Tropism Robin A. Weiss Department of Immunology and

More information

Received 18 December 2005/Accepted 12 January 2006

Received 18 December 2005/Accepted 12 January 2006 JOURNAL OF VIROLOGY, Apr. 2006, p. 3684 3691 Vol. 80, No. 7 0022-538X/06/$08.00 0 doi:10.1128/jvi.80.7.3684 3691.2006 Copyright 2006, American Society for Microbiology. All Rights Reserved. Genetic and

More information

Introduction to proteins and protein structure

Introduction to proteins and protein structure Introduction to proteins and protein structure The questions and answers below constitute an introduction to the fundamental principles of protein structure. They are all available at [link]. What are

More information

SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION doi:10.1038/nature19102 Supplementary Discussion Benzothiazepine Binding in Ca V Ab Diltiazem and other benzothiazepines inhibit Ca V 1.2 channels in a frequency-dependent manner consistent with pore block

More information

Anti-HIV Activity of Modified Milk Proteins and Fragments Thereof Dr. René Floris, NIZO Food Research, The Netherlands

Anti-HIV Activity of Modified Milk Proteins and Fragments Thereof Dr. René Floris, NIZO Food Research, The Netherlands Anti-HIV Activity of Modified Milk Proteins and Fragments Thereof Dr. René Floris, NIZ Food Research, The Netherlands René Floris has studied chemistry at Leiden University and obtained his PhD degree

More information

Bioinformatics for molecular biology

Bioinformatics for molecular biology Bioinformatics for molecular biology Structural bioinformatics tools, predictors, and 3D modeling Structural Biology Review Dr Research Scientist Department of Microbiology, Oslo University Hospital -

More information

Chapter 5. Generation of lymphocyte antigen receptors

Chapter 5. Generation of lymphocyte antigen receptors Chapter 5 Generation of lymphocyte antigen receptors Structural variation in Ig constant regions Isotype: different class of Ig Heavy-chain C regions are encoded in separate genes Initially, only two of

More information

Microbiology 507. Immune Response to Pathogens. Topics in Molecular Pathogenesis and Immunology. Zakaria Hmama, PhD UBC - Department of Medicine

Microbiology 507. Immune Response to Pathogens. Topics in Molecular Pathogenesis and Immunology. Zakaria Hmama, PhD UBC - Department of Medicine Microbiology 507 Topics in Molecular Pathogenesis and Immunology Immune Response to Pathogens Zakaria Hmama, PhD UBC - Department of Medicine October 2012 ecture 1 Mechanisms of HIV pathogenesis 1- History

More information

Viral Genetics. BIT 220 Chapter 16

Viral Genetics. BIT 220 Chapter 16 Viral Genetics BIT 220 Chapter 16 Details of the Virus Classified According to a. DNA or RNA b. Enveloped or Non-Enveloped c. Single-stranded or double-stranded Viruses contain only a few genes Reverse

More information

Structure and Function of Antigen Recognition Molecules

Structure and Function of Antigen Recognition Molecules MICR2209 Structure and Function of Antigen Recognition Molecules Dr Allison Imrie allison.imrie@uwa.edu.au 1 Synopsis: In this lecture we will examine the major receptors used by cells of the innate and

More information

number Done by Corrected by Doctor Ashraf Khasawneh

number Done by Corrected by Doctor Ashraf Khasawneh number 3 Done by Mahdi Sharawi Corrected by Doctor Ashraf Khasawneh *Note: Please go back to the slides to view the information that the doctor didn t mention. Prions Definition: Prions are rather ill-defined

More information

Supplementary Figure 1 (previous page). EM analysis of full-length GCGR. (a) Exemplary tilt pair images of the GCGR mab23 complex acquired for Random

Supplementary Figure 1 (previous page). EM analysis of full-length GCGR. (a) Exemplary tilt pair images of the GCGR mab23 complex acquired for Random S1 Supplementary Figure 1 (previous page). EM analysis of full-length GCGR. (a) Exemplary tilt pair images of the GCGR mab23 complex acquired for Random Conical Tilt (RCT) reconstruction (left: -50,right:

More information

Structural Flexibility and Functional Valence of CD4-IgG2 (PRO 542): Potential for Cross-Linking Human Immunodeficiency Virus Type 1 Envelope Spikes

Structural Flexibility and Functional Valence of CD4-IgG2 (PRO 542): Potential for Cross-Linking Human Immunodeficiency Virus Type 1 Envelope Spikes JOURNAL OF VIROLOGY, July 2001, p. 6682 6686 Vol. 75, No. 14 0022-538X/01/$04.00 0 DOI: 10.1128/JVI.75.14.6682 6686.2001 Copyright 2001, American Society for Microbiology. All Rights Reserved. Structural

More information

A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer

A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Virology Papers Virology, Nebraska Center for 4-2010 A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes

More information

Lesson 5 Proteins Levels of Protein Structure

Lesson 5 Proteins Levels of Protein Structure Lesson 5 Proteins Levels of Protein Structure Primary 1º Structure The primary structure is simply the sequence of amino acids in a protein. Chains of amino acids are written from the amino terminus (N-terminus)

More information

Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target

Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target Laura M. Walker, 1 * Sanjay K. Phogat, 2 * Po-Ying Chan-Hui, 3 Denise Wagner, 2 Pham Phung, 4 Julie L. Goss,

More information

IMMUNOBIOLOGY, BIOL 537 Exam # 2 Spring 1997

IMMUNOBIOLOGY, BIOL 537 Exam # 2 Spring 1997 Name I. TRUE-FALSE (1 point each) IMMUNOBIOLOGY, BIOL 537 Exam # 2 Spring 1997 Which of the following is TRUE or FALSE relating to immunogenicity of an antigen and T and B cell responsiveness to antigen?

More information

Discovery. Gerry Graham* and Rob Nibbs SUMMARY BACKGROUND

Discovery. Gerry Graham* and Rob Nibbs SUMMARY BACKGROUND D6 Gerry Graham* and Rob Nibbs Cancer Research Campaign Laboratories, The Beaton Institute for Cancer Research, Garscube Estate Switchback Road, Bearsdon, Glasgow G61 1BD, UK * corresponding author tel:

More information

The T cell receptor for MHC-associated peptide antigens

The T cell receptor for MHC-associated peptide antigens 1 The T cell receptor for MHC-associated peptide antigens T lymphocytes have a dual specificity: they recognize polymporphic residues of self MHC molecules, and they also recognize residues of peptide

More information

The author hereby certifies that the use of any copyrighted material in the dissertation entitled:

The author hereby certifies that the use of any copyrighted material in the dissertation entitled: The author hereby certifies that the use of any copyrighted material in the dissertation entitled: Characterization and Enhanced Processing of Soluble, Oligomeric gp140 Envelope Glycoproteins Derived from

More information

Lecture Readings. Vesicular Trafficking, Secretory Pathway, HIV Assembly and Exit from Cell

Lecture Readings. Vesicular Trafficking, Secretory Pathway, HIV Assembly and Exit from Cell October 26, 2006 1 Vesicular Trafficking, Secretory Pathway, HIV Assembly and Exit from Cell 1. Secretory pathway a. Formation of coated vesicles b. SNAREs and vesicle targeting 2. Membrane fusion a. SNAREs

More information

Structure of proteins

Structure of proteins Structure of proteins Presented by Dr. Mohammad Saadeh The requirements for the Pharmaceutical Biochemistry I Philadelphia University Faculty of pharmacy Structure of proteins The 20 a.a commonly found

More information

BCH Graduate Survey of Biochemistry

BCH Graduate Survey of Biochemistry BCH 5045 Graduate Survey of Biochemistry Instructor: Charles Guy Producer: Ron Thomas Director: Glen Graham Lecture 10 Slide sets available at: http://hort.ifas.ufl.edu/teach/guyweb/bch5045/index.html

More information

Structure of the measles virus hemagglutinin bound to the CD46 receptor. César Santiago, María L. Celma, Thilo Stehle and José M.

Structure of the measles virus hemagglutinin bound to the CD46 receptor. César Santiago, María L. Celma, Thilo Stehle and José M. Supporting Figures and Table for Structure of the measles virus hemagglutinin bound to the CD46 receptor César Santiago, María L. Celma, Thilo Stehle and José M. Casasnovas This PDF file includes: Supplementary

More information

Sheet #5 Dr. Mamoun Ahram 8/7/2014

Sheet #5 Dr. Mamoun Ahram 8/7/2014 P a g e 1 Protein Structure Quick revision - Levels of protein structure: primary, secondary, tertiary & quaternary. - Primary structure is the sequence of amino acids residues. It determines the other

More information

Protein Secondary Structure

Protein Secondary Structure Protein Secondary Structure Reading: Berg, Tymoczko & Stryer, 6th ed., Chapter 2, pp. 37-45 Problems in textbook: chapter 2, pp. 63-64, #1,5,9 Directory of Jmol structures of proteins: http://www.biochem.arizona.edu/classes/bioc462/462a/jmol/routines/routines.html

More information

White Blood Cells (WBCs)

White Blood Cells (WBCs) YOUR ACTIVE IMMUNE DEFENSES 1 ADAPTIVE IMMUNE RESPONSE 2! Innate Immunity - invariant (generalized) - early, limited specificity - the first line of defense 1. Barriers - skin, tears 2. Phagocytes - neutrophils,

More information

Week 5 Section. Junaid Malek, M.D.

Week 5 Section. Junaid Malek, M.D. Week 5 Section Junaid Malek, M.D. HIV: Anatomy Membrane (partiallystolen from host cell) 2 Glycoproteins (proteins modified by added sugar) 2 copies of RNA Capsid HIV Genome Encodes: Structural Proteins

More information

all of the above the ability to impart long term memory adaptive immunity all of the above bone marrow none of the above

all of the above the ability to impart long term memory adaptive immunity all of the above bone marrow none of the above 1. (3 points) Immediately after a pathogen enters the body, it faces the cells and soluble proteins of the innate immune system. Which of the following are characteristics of innate immunity? a. inflammation

More information

Quantification of CCR5 mrna in Human Lymphocytes and Macrophages by Real-Time Reverse Transcriptase PCR Assay

Quantification of CCR5 mrna in Human Lymphocytes and Macrophages by Real-Time Reverse Transcriptase PCR Assay CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, Nov. 2003, p. 1123 1128 Vol. 10, No. 6 1071-412X/03/$08.00 0 DOI: 10.1128/CDLI.10.6.1123 1128.2003 Copyright 2003, American Society for Microbiology. All

More information

HIV & AIDS: Overview

HIV & AIDS: Overview HIV & AIDS: Overview UNIVERSITY OF PAPUA NEW GUINEA SCHOOL OF MEDICINE AND HEALTH SCIENCES DIVISION OF BASIC MEDICAL SCIENCES DISCIPLINE OF BIOCHEMISTRY & MOLECULAR BIOLOGY PBL SEMINAR VJ TEMPLE 1 What

More information

IMMUNE CELL SURFACE RECEPTORS AND THEIR FUNCTIONS

IMMUNE CELL SURFACE RECEPTORS AND THEIR FUNCTIONS LECTURE: 07 Title: IMMUNE CELL SURFACE RECEPTORS AND THEIR FUNCTIONS LEARNING OBJECTIVES: The student should be able to: The chemical nature of the cellular surface receptors. Define the location of the

More information