Download presentation
Presentation is loading. Please wait.
Published byThomasine Bryan Modified over 8 years ago
1
Immunology of HIV Rupert Kaul
2
“The immunology of HIV” 1.Review of HIV-1, life cycle, transmission 2.How does HIV infect a person? Mucosal immune events 3.How does HIV cause disease? Direct vs bystander, gut events 4.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 10 9 viruses produced per day, error-prone reverse transcriptase (q 10 -4 -10 -5 )
5
(1) HIV-1 attachment; (2) Fusion; (3) Cell entry; (4) Reverse transcription, formation of the pre-integration complex (PIC); (5) Nuclear transport; (6) Chromosomal integration of DNA provirus; (7) Transcription of viral RNA; (8) Nuclear export of RNA; (9) Translation and processing; (10) Membrane transport; (11) Virion assembly; (12) Budding; (13) Maturation. HIV-1 life cycle
6
HIV - clinical progression
7
Two contrasting facts: HIV has spread widely and rapidly…
8
UK PEP Guidelines, 2006. …and yet HIV is relatively difficult to transmit
9
Blood viral load correlates with transmission. Quinn, T. 2000.
10
Blood HIV levels predict amount of virus in “genital fluids” Sheth P; J Immunol, 2005.Kovacs A; Lancet, 2001.
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
Hladik F. Immunity, 2007. Haase A. Nat Imm Rev, 2005. What are the major genital HIV targets?
13
Penile HIV target cells
14
Mucosal immune protection vs HIV… Viewpoint. Coates T, et al. Lancet, 2007. 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 Freeman E, AIDS, 2006;
16
Cervical target cells in HIV(-) women These associations were seen in HSV-2 infected women in the absence of HSV-2 DNA shedding or clinically apparent ulceration
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
Mehandru et al. PLoS Med, 2006. HIV: immune effects on the gut Brenchley et al. JEM, 2004
19
4 7 and HIV infection Johnson P. NEJM, 2008. Mora J. Nature, 2003.
20
Gut events and HIV pathogenesis Brenchley J. Nat Med, 2006. HYPOTHESIS: GI mucosal immune defects bacterial translocation systemic immune activation CD4 depletion.
21
Bacterial translocation and inflammation Silvestri G. AIDS Rev, 2008. Systemic inflammation correlates closely with both: –Bacterial translocation –Rate of CD4 depletion
22
Non-pathogenic SIV models: Sooties and AGMs Silvestri G. Blood, 2008; Immunity, 2003
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
27
Wei X. Nature, 2003.
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
31
Sewell A 2001
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
34
Kiepela et al. Nature, 2004
35
CTL: not good enough… 1.Proviral latency - no antigen expressed 2.Downregulation of HLA class I (nef, vpu) 3.Upregulation of Fas ligand 4.Mutation: epitope mutation prevents HLA binding, TLR binding flanking mutations prevent processing BUT do see benefits from a “less fit” virus 5.Impaired CD8+ function
36
Escape from CTL control Mutation:Other:
38
Ahmed R, et al. J Exp Med, 2006. 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 Betts, M Blood, 2006 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 1.Resistance to acquisition is the norm 2.Gut events / immune activation and disease 3.Cellular responses are primarily responsible for (inadequate) control post-infection 4.Antibody responses against specific epitopes may provide passive protection 5.Circumcision is an effective mucosal intervention
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.