Immunology of HIV
Rupert Kaul
“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
HIV structure
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)
HIV-1 life cycle
(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 - clinical progression
Two contrasting facts:
HIV has spread widely and rapidly…
…and yet HIV is relatively difficult to transmit
UK PEP Guidelines, 2006.
Blood viral load correlates with transmission.
Quinn, T.
2000.
Blood HIV levels predict amount of
virus in “genital fluids”
Sheth P; J Immunol, 2005.
Kovacs A; Lancet, 2001.
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
What are the major genital HIV targets?
Hladik F. Immunity, 2007.
Haase A. Nat Imm Rev, 2005.
Penile HIV target cells
Mucosal immune protection vs HIV…
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•
•
•
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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
Viewpoint.
Coates T, et al.
Lancet, 2007.
Mucosal immunology and coinfections
Freeman E, AIDS, 2006;
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
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
HIV: immune effects on the gut
Mehandru et al.
PLoS Med, 2006.
Brenchley et al.
JEM, 2004
47 and HIV infection
Mora J.
Nature, 2003.
Johnson P. NEJM, 2008.
Gut events and HIV pathogenesis
HYPOTHESIS:
• GI mucosal
immune defects
 bacterial
translocation 
systemic immune
activation  CD4
depletion.
Brenchley J.
Nat Med, 2006.
Bacterial translocation and
inflammation
• Systemic inflammation
correlates closely with both:
– Bacterial translocation
– Rate of CD4 depletion
Silvestri G. AIDS Rev, 2008.
Non-pathogenic SIV models:
Sooties and AGMs
Silvestri G.
Blood, 2008; Immunity, 2003
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
Host defenses: antibodies
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
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
Wei X.
Nature, 2003.
HIV antibody responses (3)
• BUT: some are specific for conserved regions, do
neutralize primary virus, synergize
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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
Host defenses: CTL
Sewell A
2001
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
Immune time course post
infection
Kiepela et al.
Nature, 2004
CTL: not good enough…
1.
2.
3.
4.
Proviral latency - no antigen expressed
Downregulation of HLA class I (nef, vpu)
Upregulation of Fas ligand
Mutation:
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•
•
epitope mutation prevents HLA binding, TLR binding
flanking mutations prevent processing
BUT do see benefits from a “less fit” virus
5. Impaired CD8+ function
Escape from CTL control
Mutation:
Other:
Cellular immune “exhaustion”
Ahmed R, et al. J Exp Med, 2006.
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)
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
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
Polyfunctionality and survival
Progressors
LTNP
Betts, M
Blood, 2006
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
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
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