Immunology of HIV

Rupert Kaul

“The immunology of HIV”

1. Review of HIV-1, life cycle, transmission2. 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)

(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

HIV - clinical progression

Two contrasting facts:

HIV has spread widely and rapidly…

UK PEP Guidelines, 2006.

…and yet HIV is relatively difficult to transmit

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

Hladik F. Immunity, 2007.

Haase A. Nat Imm Rev, 2005.

What are the major genital HIV targets?

Penile HIV target cells

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

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

Mehandru et al. PLoS Med, 2006.

HIV: immune effects on the gut

Brenchley et al. JEM, 2004

47 and HIV infection

Johnson P. NEJM, 2008.

Mora J.Nature, 2003.

Gut events and HIV pathogenesis

Brenchley J. Nat Med, 2006.

HYPOTHESIS:• GI mucosal

immune defects bacterial translocation systemic immune activation CD4 depletion.

Bacterial translocation andinflammation

Silvestri G. AIDS Rev, 2008.

• Systemic inflammation correlates closely with both:– Bacterial translocation– Rate of CD4 depletion

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 – 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 A2001

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. Proviral latency - no antigen expressed2. 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

Escape from CTL control

Mutation: Other:

Ahmed R, et al. J Exp Med, 2006.

Cellular immune “exhaustion”

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

Betts, MBlood, 2006

Progressors

LTNP

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 norm2. Gut events / immune activation and disease3. Cellular responses are primarily responsible for

(inadequate) control post-infection4. Antibody responses against specific epitopes

may provide passive protection 5. Circumcision is an effective mucosal

intervention