Innate and Cellular Immunology Control of Infection by Cell-mediated Immunity

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1 Innate & adaptive Immunity Innate and Cellular Immunology Control of Infection by Cell-mediated Immunity Helen Horton PhD Seattle Biomedical Research Institute Depts of Global Health & Medicine, UW Cellular & Molecular Immunology. Authors: Abul K. Abbas, Andrew H. Lichtman, & Shiv Pillai How do T cells see HIV-infected cells?: Major Histocompatibility Complex (MHC) How do CD8+ T cells see HIV-infected targets? MHC proteins anchor fragments of pathogens (epitopes) onto the surface of an infected cell so that they can be detected by T cells MHC in humans is called human leukocyte antigen (HLA) CD8+ T cells recognize infected cells through interactions with MHC class I bound to viral peptides. HLA class I: - expressed on virtually all nucleated cells - recognized by CD8+ CTL - 3 loci: A, B, C The HIV-specific T cell recognizes both the viral peptide and the specific MHC molecule displaying it. HLA class II: - expressed on limited number of immune cells with antigen-presenting capability - recognized by CD4+ helper T lymphocytes (HTL) What qualities make an effective T cell? CTL recognition leads to release of granzyme and perforin from the CTL. Epitopes targeted Intuitively HIV-specific T cells that target conserved epitopes of HIV-1 would be superior to those that target variable epitopes Proliferative capacity LTNP possess HIV-specific T cells with greater proliferative capacity than T cells from progressors (Migueles et al. Nat Immunol 2002) Polyfunctionality Perforin punches holes in membranes of the infected cell. Granzymes destroy the cellular contents. LTNP possess HIV-specific T cells with greater functionailty than T cells from progressors (Betts et al. Blood 2006) Adapted from Gary Kaiser: 1

2 Methodologies to Measure HIV-specific T cells Epitopes targeted ELISpot is used to identify HIV-1 epitopes recognized Anti-IFNγ coated plate PBMC and HIV peptides added IFN-γ ELISpot assays Tetramer staining T cells specific for peptide secrete IFNγ IFNγ bound by Ab on plate Proliferative capacity CFSE dilution assays PBMC washed away Secondary labeled anti-ifnγ Ab added Polyfunctionality Intracellular cytokine staining assays Substrate added Each spot corresponds to a cell that Secreted IFNγ in response to an HIV epitope Tetramer Staining enumerates specific T cells Proliferation is measured using carboxyfluorescein diacetate, succinimidyl ester (CFSE) RK9/A*03 tetramers will bind specifically to CD8+ T cells that recognize RK9 in the context of HLA-A*03 Control RK9-specific T cells CFSE Intracellular Cytokine Assay (ICS) Innate & adaptive Immunity Cellular & Molecular Immunology. Authors: Abul K. Abbas, Andrew H. Lichtman, & Shiv Pillai 2

3 How do NK cells kill their targets? Can NK cells control HIV? Different NK activities are regulated by receptor families including the Killer-cell Immuno-globulin-like Receptors (KIR). KIR3DS1 (an activating KIR) has been associated with slow progression to AIDS in individuals with Bw4-I80 HLA (Martin et al; Nat Gen 2002) Do certain HLA/KIR combinations make for superior NK cells?!"#$%&' ()*+ #,-./(-01$2)$ $.780,-01$, ,:0-06$,;-<4.706=,>0?<4.706!"#$%&'()*+!)F$F",)-$./01!"#$.)*+.)*+ # $9,$( :4;;<$4=>72378$27;;<? 2)$7<-$(,-./(-01 What qualities make an effective NK cell? Ability to kill HIV-infected cells Ability to secrete anti-viral cytokines/ chemokines Methodologies to Measure NK cell activity Ability to kill HIV-infected cells Cytotoxicity assays Viral suppression assays Antibody-dependent cellular cytoxicity Ability to secrete anti-viral cytokines/ chemokines Intracellular cytokine staining assays (ICS) Luminex Cytotoxicity (killing) Assay Viral Suppression Assay (VSA) 3

4 Antibody-dependent cellular cytotoxicity (ADCC) Luminex Assay for Cytokine Measurements Immune Control of HIV- Does it exist? Long-Term Nonprogressors (LTNP) Control of Infection by Cellmediated Immunity Does it exist and can vaccines induce it? In our study LTNP are individuals who have been HIV-1-infected for more than 11 years have sustained viral loads <10,000 copies/ml Are not receiving ART. LTNP constitute less than 1% of all HIV-infected persons. LTNP appear to be able to control HIV replication and are spared from disease progression. HLA-B27 (24% vs. 4%) and HLA-B57 (59% vs. 3%) are highly associated with LTNP implicating a role for CD8+ T cells in control of HIV infection. Can HIV-specific T cell immunity control of HIV-1? FOR: CD8+ T cells have been implicated in control of HIV (depletion studies in RM; Jin et al, 1999) Certain HLA alleles, notably B27 and B57 are associated with HIV control and non-progression Vast literature on CTL escape Escape in the B27-restricted KK10 epitope correlates with progression to disease AGAINST: The frequency of IFN-γ-secreting HIV-specific T cells does not correlate with control of HIV (Cao et al, 2003; Addo et al, 2003) are we measuring the wrong function? What qualities make an effective T cell? Epitopes targeted Intuitively HIV-specific T cells that target conserved epitopes of HIV-1 would be superior to those that target variable epitopes Proliferative capacity LTNP possess HIV-specific T cells with greater proliferative capacity than T cells from progressors (Migueles et al. Nat Immunol 2002) Polyfunctionality LTNP possess HIV-specific T cells with greater functionailty than T cells from progressors (Betts et al. Blood 2006) 4

5 Majority of epitopes targeted during early infection are variable B27-restricted epitopes are more highly conserved than B35- restricted epitopes Conservation score: the frequency of the exact epitope in all HIV-1 sequences in the LANL database B27 & B57 are associated with non-progression B35Px is associated with rapid progression Allele Epitope Conservation score B27 Gag KRWIILGLNK 0.87 Pol FKRKGGIGGY 0.86 Subject # HLA-A A*01/29 A*02/02 A*01/68 A*01/03 A*29/32 A*02/11 A*01/01 A*01/03 A*24/24 A*03/11 A*23/26 A*02/02 HLA-B B*38/44 B*27/49 B*40/57 B*08/35 B*35/44 B*27/40 B*07/15 B*07/37 B*35/38 B*35/53 B*38/38 B*07/44 HLA-C C*12/16 C*02/07 C*03/06 C*04/07 C*04/16 C*02/02 C*02/07 C*06/07 C*04/12 C*04/04 C*04/12 C*07/07 B57 Nef HTQGYFPDW 0.36 Gag ISPRTLNAW 0.59 Pol IVLPEKDSW 0.14 Gag KAFSPEVIPMF 0.84 Gag TSTLQEQIGW 0.40 B35Px Env DPNPQEVVL 0.12 Pol IPLTEEAEL 0.09 Targeting conserved epitopes correlates with longer survival What qualities make an effective T cell? Epitopes targeted Intuitively HIV-specific T cells that target conserved epitopes of HIV-1 would be superior to those that target variable epitopes Years of infection Survival fraction Proliferative capacity LTNP possess HIV-specific T cells with greater proliferative capacity than T cells from progressors (Migueles et al. Nat Immunol 2002) Polyfunctionality LTNP possess HIV-specific T cells with greater functionailty than T cells from progressors (Betts et al. Blood 2006) Dinges et al, JV In press Proliferative ability of HIV-1-specific CD8+ T cells correlates with HIV-1 control Perforin increases when T cells proliferate presumably proliferation of antigenspecific T cells is, therefore, linked to their ability to kill infected targets. HIV-specific T cells from LTNP can proliferate whereas those from progressors cannot. Most HIV-specific T cells become tolerant during chronic infection Will HIV-specific T cells induced by vaccination be able to proliferate? 4 HIV-1 seronegative HLA-A03 + vaccinees had CD8 + T cells that recognize the HLA A03-restricted RLRPGGKKK (RK9) epitope from HIV-1 Gag. 12 HIV-1-infected individuals from different longitudinal cohorts also possess T cells specific for RK9. Note that we are looking at epitope-specific responses not bulk HIV-specific responses. Progressors LTNP Migueles et al. Nat Immunol

6 Patient Samples Flow Cytometric Methods PTID Status VL CD4 DPI NP13 LTNP < yrs NP22 LTNP < yrs NP23 LTNP < yrs NP14 LTNP 2, yrs NP20 chronic 57, yrs C1094 chronic 86, yrs SAC13 chronic <50 (on ART) yrs C1238 early 3,999(on ART) mo C1396 early 8,199(on ART) days C1596 early 260, days SAC12 early 65, mo Tetramer staining enumerates the total number of RK9- specific T cells regardless of their function Intracellular cytokine staining enumerates CD8 + T cells that secrete IFN-γ, TNF-α, IL2, etc in response to RK9 peptide (measures polyfunctionality) CFSE dilution assays measure proliferative capacity of CD8 + RK9-specific T cells What we anticipated: From Migueles et al: LTNP RK9-specific T cells will proliferate. chronically-infected individuals RK9-specific T cells will not proliferate. Vaccinees? We hoped they would proliferate like T cells from LTNP What we got Q: Is lack of proliferative ability but maintenance of cytokine secretion due to chronic prolonged infection? Q: Why did RK9-specific T cells from LTNP fail to proliferate? Are T cells differentially sensitive to tolerance? Inability to proliferate occurs due to chronic prolonged infection By day 1621 of infection, RK9-specific T cells can still secrete IFN-γ and TNF-α, but can no longer proliferate (corroborated by cross-sectional studies by Lichterfeld et al, 2004)

7 Why are LTNP able to control infection? (Horton et al JI 2006) Are HIV-specific T cells differentially sensitive to tolerance (i.e. can some be tolerized more easily then others)? HLA-B27 and -B57 are associated with non-progression Can B57/B27-restricted T cells proliferate more than T cells restricted by other alleles (i.e. are they resistant to tolerance) within the same individual? HIV-Specific CD8 + T cells Restricted by HLA B27 and/or B57 Proliferate more than HIV-Specific CD8 + T cells Restricted by Other HLA alleles LTNP possess HIV-specific T cells that: Proliferate Are polyfunctional Target conserved epitopes Do vaccine-induced HIV-specific T cells have all these qualities? (Horton et al JI 2006) HVTN 054: Phase I Dose Escalation Trial Number of 15mer peptides recognized Vaccine: 1 dose of Ad5 (NIH Vaccine Research Center) encoding Gag/Pol (clade B), Env (clades A,B,C) Study Participants: n= 48, low Ad5 neutralizing Ab titers Study Design: Group 1: 20/4: PU vaccine/placebo Group 2: 20/4: PU vaccine/placebo PBMC Cryopreservation: within 8 hours after venipuncture on site Immunogenicity Assessment: ELISpot, ICS at day 28 with Global PTE peptides (160 peptides per pool, 8 pools) # of # of Volunteers Responses >6 3 34/40 vaccinees mounted HIVspecific T cell responses. Median # epitopes recognized by individuals with acute HIV-1 infection 2 (range 0-5; Altfeld et al 2001) 2 (range 0-6; Cao et al 2003) 4 (range: 2-7; Addo et al 2003) 7

8 All CD8+ T cells induced by vaccination are polyfuntional regardless of epitope recognized or MHC restriction All CD8+ T cells induced by vaccination can proliferate regardless of epitope recognized or MHC restriction B35 A30 A30 4 Functions 3 Functions 2 Functions 1 Function CD107a IFNγ IL2 TNFα B27 B35 B35 A29 But vaccine-induced HIV-specific T cells predominantly target variable epitopes Subtype A Subtype B Subtype C What about the Merck Vaccine? 50/73 (68%) of the vaccinated individuals who subsequently became infected possessed vaccine-induced HIV-specific T cells prior to infection. Subtype A Subtype B Subtype C Even individuals recognizing many HIV-specific epitopes still became infected Note: This is not the Merck vaccine. Mapping of the epitopes recognized by T cells induced by the Merck vaccine has just recently been completed Median # epitopes recognized was similar to the VRC vaccine Nicole Frahm, HVTN Challenges related to HIV Vaccine Research Conclusions To determine efficacy, trials need to be conducted in areas with high transmission rates (e.g. sub-saharan Africa) Mapping epitopes recognized by T cells is very cell intensive It is expensive to draw and process large blood draws Logistic difficulties (cells must be frozen within 8 hrs of draw) There are ethnic concerns re large blood draws and removal of cells from the home country It would be helpful to have more in-country lab expertise so that assays could be performed at the vaccine site **We still don t know the correlates of protection More basic research on e.g. LTNP, exposed seronegatives Not all T cells are created equally: Studies on LTNP have shown us that protective T cell responses can proliferate, are polyfunctional and target conserved epitopes. To date all vaccine-induced HIV-specific T cells Are polyfunctional with regard to cytokine secretion Possess proliferative capacity However, the majority of HIV-1 epitopes targeted after vaccination are variable (unlike B27- and B57- restricted responses) suggests that candidate immunogens should be redesigned to contain only conserved regions 8

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