Attachment and Entry. Lecture 5 Biology W3310/4310 Virology Spring Who hath deceived thee so o-en as thyself? --BENJAMIN FRANKLIN

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1 Attachment and Entry Lecture 5 Biology W3310/4310 Virology Spring 2016 Who hath deceived thee so o-en as thyself? --BENJAMIN FRANKLIN

2 Viruses are obligate intracellular parasites Virus particles are too large to diffuse across the plasma membrane Principles of Virology, ASM Press

3 Finding the right cell Step 1: adhere to cell surface (electrostatics) - No specificity Step 2: Attach to specific receptor molecules on cell surface - More than one receptor may be involved Step 3: Transfer genome inside the cell

4 Cellular receptors for viruses Essential for all viruses except those of fungi (no extracellular phases) and plants (enter cells by mechanical damage) 1985: one receptor known, sialic acid for influenza virus

5 Cytoplasm Indirectly anchored protein Outside of cell Carbohydrate Integral membrane proteins Lipid-anchored protein Cytoplasm Indirectly anchored protein AAV HPV HSV VACV IAV Measles RSV RV SV40 Galactose Sialic acid GlcNAc GalNAc HCV HRV2 LDL-like DV EBOV KSHV UUKV FMDV HCMV KSHV RV HIV1 HAdV 2/5 Glucose HSPG Sialic acid GM1 ganglioside LDLR DC-SIGN Integrin αvβ3 CD4 CCR5 CXCR4 Car Integrin αvβ3 or 5 Attachment factors ScEYEnce Studios Principles of Virology, 4e Receptors Principles of Virology, ASM Press

pseudorabies virus, binds same receptor as human poliovirus Viruses of

6 Different viruses can bind the same receptor Adenovirus and Coxsackievirus B3 have common primary receptor The swine herpesvirus, pseudorabies virus, binds same receptor as human poliovirus Viruses of the same family may bind different receptors: rhinoviruses (3), retroviruses (16)

7 Viruses of the same family may bind different receptors Viruses of the same family may bind different receptors: rhinoviruses (3), retroviruses (16) One virus may bind multiple receptors Principles of Virology, ASM Press

8 Principles of Virology, ASM Press

9 Principles of Virology, ASM Press

10 Influenza virus attachment to cells Neuraminidase (NA) Hemagglutinin (HA) Principles of Virology, ASM Press

11 Sialic acid: receptor for influenza viruses Sialic acids: N-acetylneuraminic acid (A,B); 9-Oacetyl-N-neuraminic acid (C) α(2,6) preferentially used by human strains, α(2,3) by avian Principles of Virology, ASM Press

12 Monomer of influenza HA protein Principles of Virology, ASM Press

13 HIV-1 attachment Principles of Virology, ASM Press

14 Go to: m.socrative.com room number: virus Viral receptors on the cell surface: 1. Can bind directly to icosahedral virus capsid proteins 2. Interact with glycoproteins of enveloped viruses 3. Can be carbohydrate or protein molecules 4. Have cellular functions 5. All of the above 1

15 Entry into cells Principles of Virology, ASM Press

16 The cytoplasm is crowded! Movement of large protein complexes will not occur by diffusion! Principles of Virology, ASM Press

17 Principles of Virology, ASM Press

18 Movement of endosomes XVIVO Scien6fic Anima6on h<p://

19 Principles of Virology, ASM Press

21 molecularmovies.org

22 Go to: m.socrative.com room number: virus Which of the following does not play a role in virus entry: 1. Clathrin-mediated endocytosis 2. Fusion of viral and plasma membranes 3. Diffusion of virus particles in the cytoplasm 4. Microtubule-mediated transport 5. Lysosomes 2

23 Principles of Virology, ASM Press

24 Principles of Virology, ASM Press

25 Class I fusion proteins Perpendicular to membrane - spikes Mostly α-helical Form trimers Principles of Virology, ASM Press

26 Influenza virus entry

27 Class II fusion proteins Mostly β-sheet Form dimers Parallel to the membrane Principles of Virology, ASM Press

28 Dengue virus entry

29 Ebolavirus entry Principles of Virology, ASM Press

Fusion is regulated Must not occur in the wrong location Neutral ph (plasma membrane): - Second protein receptor interaction Low ph fusion - Proteolytic cleavage activates

30 Fusion is regulated Must not occur in the wrong location Neutral ph (plasma membrane): - Second protein receptor interaction Low ph fusion - Proteolytic cleavage activates the fusion protein for cleavage (class I) - Cleavage of a second protein (class II) activates the fusion protein - Endosome fusion receptor Principles of Virology, ASM Press

31 Go to: m.socrative.com room number: virus Viral fusion peptides are exposed for insertion into the host cell membrane when: 1. The virus particle is near a cell 2. The virus particle is in the cytoplasm 3. Trimers of the fusion peptides form 4. The endosome becomes acidified 5. The virus is docked on the nuclear pore 3

32 Principles of Virology, ASM Press

33 Principles of Virology, ASM Press

34 Principles of Virology, ASM Press

receptor) These viruses initiate infection at the epithelial surface CAR is a component of

35 Role of a co-receptor in viral infection Entry of Coxsackievirus group B viruses requires two receptors: decay-accelerating factor (DAF), and CAR (coxsackievirus-adenovirus receptor) These viruses initiate infection at the epithelial surface CAR is a component of tight junctions, not accessible to viruses on the apical surface Principles of Virology, ASM Press

37 Principles of Virology, ASM Press

38 Principles of Virology, ASM Press

39 Principles of Virology, ASM Press

40 Principles of Virology, ASM Press

Virus Entry/Uncoating

Virus Entry/Uncoating Delivery of genome to inside of a cell Genome must be available for first step of replication The Problem--barriers to infection Virion Barriers: Non-enveloped viruses capsid Enveloped