Immunology of HIV

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Immunology of HIV

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1. Immunology of HIV Rupert Kaul

2. “The immunology of HIV” Review of HIV-1, life cycle, transmission How does HIV infect a person? Mucosal immune events How does HIV cause disease? Direct vs bystander, gut events How does the host fight back? Implications for vaccines, therapeutics

3. HIV structure

4. HIV - virus, genetics HIV is a lentivirus - an RNA virus from the class of retroviruses 2 HIV species (1 and 2) - 40-50% homologous Several HIV clades - A,B,C,D,A/E,O (others) - 70-80% homologous Within a clade - 85-90% homologous Within an individual - “quasispecies” >95% homologous About 109 viruses produced per day, error-prone reverse transcriptase (q 10-4-10-5)

5. HIV-1 life cycle

6. HIV - clinical progression

7. Two contrasting facts: HIV has spread widely and rapidly…

8. …and yet HIV is relatively difficult to transmit

10. Blood HIV levels predict amount of virus in “genital fluids”

11. Genital/mucosal protective factors Genital tract repels >99% of HIV exposures Combination of factors: Intact epithelium Mucus, pH, SLPI, lactoferrin, Trappin-2, etc ?Adaptive mucosal immunity Lack of co-infections also important

12. What are the major genital HIV targets?

13. Penile HIV target cells

14. Mucosal immune protection vs HIV… 3 large RCTs in SSA showed clear benefit Very consistent results in Uganda, Kenya, SA Efficacy: ITT ~55%, OTA ~63% In Kenya: incidence 2.1% vs 4.2% No short term behavioural disinhibition is being followed prospectively

15. Mucosal immunology and coinfections

17. How does HIV cause disease? Not direct depletion of CD4+ T cells See a number of immune effects that contribute: Increased immune activation ? Via switched on innate immunity, ? damage to gut mucosa Leads to skewed T cell function, apoptosis Loss/dysfunction of many cell types: pDCs, other dendritic cell subsets CD4 and CD8 T cells NK cells, NKT cells, GD cells, etc etc

18. HIV: immune effects on the gut

19. ?4?7 and HIV infection

20. Gut events and HIV pathogenesis HYPOTHESIS: GI mucosal immune defects ? bacterial translocation ? systemic immune activation ? CD4 depletion.

21. Bacterial translocation and inflammation Systemic inflammation correlates closely with both: Bacterial translocation Rate of CD4 depletion

22. Non-pathogenic SIV models: Sooties and AGMs

23. Lessons from non-pathogenic models* Do not see enhanced cellular immunity Do see reduced inflammation - initial “blip”, rapidly downregulated Do see CD4+ depletion in the gut, but transient and then recovers Target “shielding”?? SM - reduced CCR5 expression if activated AGM - “CD4(-)” T helpers not depleted

24. Host defenses: antibodies

25. HIV: antibody responses IgG response is ubiquitous - basis of diagnosis Most people do make neutralizing Abs against their own virus BUT only work against the virus that was there a few months ago - not the one that is there today Failure of infused “cocktail” to impact infection for more than a few days

26. HIV antibody responses (2) Conformational masking - entropy Lack of broad neutralization Shielding of highly-conserved coreceptor binding regions by hypervariable loops “Irrelevant" antibodies vs gp120 monomers, or non-critical regions of the gp120-trimer (debris) Surface glycosylation: focused changes in glycan packing prevent neutralizing Ab binding but not receptor binding

28. HIV antibody responses (3) BUT: some are specific for conserved regions, do neutralize primary virus, synergize F105, b12 - CD4 binding site of gp120 2G12 - complex gp120 epitope 2F5, 4E10, Z13 - gp41 OTHERS just described **Passive infusion of cocktail = ONLY model of sterilizing immunity (MCH, PEP trials) ?Pre-formed Ab applicable via microbicides

30. Host defenses: CTL

32. CTL responses: any good? In primate models, vaccine-induced CTL can slow progression, improve viral control Timing of CTL and control CD8+ depletion experiments CTL (CD8+) impose major immune pressure on virus (SIV, HIV) HIV-specific CD4+, CD8+ responses found in exposed, uninfected populations

33. Immune time course post infection

35. CTL: not good enough… Proviral latency - no antigen expressed Downregulation of HLA class I (nef, vpu) Upregulation of Fas ligand Mutation: epitope mutation prevents HLA binding, TLR binding flanking mutations prevent processing BUT do see benefits from a “less fit” virus Impaired CD8+ function

36. Escape from CTL control

38. Cellular immune “exhaustion”

39. HIV superinfection can occur Despite strong CTL, can be infected by a second strain of HIV-1 But may be less common than initial infection ?? Half as likely to happen (very unclear)

40. Real life HIV protection? exposed uninfected individuals People who “should be infected but aren’t” sex workers, discordant couples, etc Several correlates: Lack of CCR5 HIV specific cellular immunity: lysis, IFNg, proliferation (generally low level) HIV neutralizing IgA Dampened immune activation ? Actually mediating protection vs. paraphenomenon

41. Immune correlates of HIV protection: long-term nonprogressors People who “should be sick but aren’t” Infected for >10 years, normal immune system, low VL Also “elite controllers” - low/undetectable VL Several correlates: Certain class I HLA types: B5701/03, B27, etc HIV specific cellular immunity: breadth? Function? No good humoral associations

42. Polyfunctionality and survival Progressors LTNP

43. Vaccine-induced CTL: are they useful? Macaque models - several show that inducing SIV/SHIV-specific CD8+ T cells can lower viral load, slow/prevent progression Generally don’t prevent infection - but maybe could protect against “real” challenge? Hard to induce using candidate vaccines Case of human infection post vaccine despite strong CD8+ responses against dominant epitope

44. STEP TRIAL Merck HIV vaccine Adenovirus (Ad5) based, sole goal was to induce cellular immunity Did so fairly well, BUT… No protection against infection No impact on post-infection VL Increased HIV rates if prior adeno infection

45. Summary Resistance to acquisition is the norm Gut events / immune activation and disease Cellular responses are primarily responsible for (inadequate) control post-infection Antibody responses against specific epitopes may provide passive protection Circumcision is an effective mucosal intervention

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