Protective Immunity Against HIV1

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Protective Immunity Against HIV-1

• Rupert Kaul
• University of Toronto, Canada

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The bottom line

• We dont know if there even is such a thing
• Working out the correlates of HIV immunity is
  (a) key to HIV vaccines

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HIV-1 protective immunity

• Various possible meanings
• Sterile immunity no infection after contact
• Controlling immunity infected, but do not
  develop immunosuppression
• Transmission immunity infected, but dont shed
  or transmit virus (related to 2)

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HIV transmission (1)

• Sex
• by far the most common method of transmission
  85-90 of global cases
• quite inefficient 0.3 (USA) - 3 (Thailand)
• increased via
• amount of virus in infected partners blood
• STDs (especially if ulcer)
• type of sex (anal gt vaginal gt oral)
• gender (male?female gt female?male)
• lack of male circumcision
• ?? type (clade) of virus

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Partner plasma viral load and transmission
Quinn et al. NEJM, 2000. 415 couples
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Cohen, M. J Infect Dis, 2005.
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HIV transmission (2)

• Mother-to-child
• rate without antiviral drugs for mother is 25
  in the US, 30-40 in Kenya
• most transmission (20-25) is during delivery
• breast feeding also risky (10-15) - exclusive
  breast feeding?
• risk increased by maternal STD or placentitis
• peripartum transmission reduced via C-section
• if mother is screened early and mother/baby
  treated, transmission can be reduced to 1
• Other methods
• less common globally
• blood transfusion/products
• IV drug use, contaminated needles, occupational

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HIV-1 immunity - overview

• Review of HIV-1, life cycle, transmission
• Humoral immunity
• In infected individuals - neutralization, escape,
  debris
• As an vaccine strategy - active, passive
• Cellular immunity
• In infected individuals - control, escape,
  evolution
• As a vaccine strategy - active (passive ?) - SIV,
  HIV
• Innate immunity
• Soluble factors - Trappin, SLPI, etc
• Cellular factors -TRIM5a, APOBEC, etc

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HIV structure
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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 gt95
  homologous
• About 109 viruses produced per day, error-prone
  reverse transcriptase (q 10-4-10-5)

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HIV cell entry 101

• This is what happens systemically
• Not sure how HIV first causes infection after sex
• ? binds CD4 and CCR5 on a CD4 cell?
• ? via DCSIGN on a dendritic cell

CCR5
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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.
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HIV - clinical progression
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(1) Humoral immunity
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HIV antibody responses (1)

• 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

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HIV antibody responses CONS

• Conformational masking
• 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

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HIV antibody responses PROS

• BUT some are specific for conserved regions, do
  neutralize primary virus, synergize - how can we
  focus humoral responses?
• F105, b12 - CD4 binding site of gp120
• 2G12 - complex gp120 epitope
• 2F5, 4E10, Z13 - gp41
• Passive infusion of cocktail ONLY model of
  sterilizing immunity (MCH, PEP trials)
• ?Pre-formed Ab applicable via microbicides

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Passive immunization effective, even 6 hours post
challenge
Nishimura Y et al. PNAS, 2003.
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• Viruses early in infection are less glycosylated,
  more easily neutralized (Overbaugh J, 2005).
• Borne out in some studies, not others

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(2) Cellular immunity
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HIV and cellular responses PROS

• In primate models, vaccine-induced CTL can slow
  progression, improve viral control
• CTL are associated with control after acute HIV
  infection
• CTL (CD8) impose major immune pressure on virus
• HIV-specific CD4, CD8 responses found in
  exposed, uninfected populations

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Immune time course post infection
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CD8 depletion and plasma SIV load
Jin X et al. J Exp Med, 1999
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Kiepela et al. Nature, 2004
Musey et al. NEJM, 1995
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Kiepela et al. Nature Medicine, 2007
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Barouch et al. Science, 2000.
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CONS HIV evasion of cellular immunity

• Proviral latency - no antigen expressed
• Downregulation of HLA class I (nef, vpu)
• Upregulation of Fas ligand - back-killing via
  apoptosis
• Mutation
• epitope mutation prevents HLA binding, TLR
  binding
• flanking mutations prevent processing
• Loss of HIV-specific T help /- persistent
  antigen - impaired CD8 function

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Escape from CTL control
Mutation
Other
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CD8 escape variants are transmissible
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Impaired CTL maturation?
May relate to persistent, high levels of antigen
(Ahmed)
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Ahmed, J Virol. 2003.
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Ahmed R, et al. J Exp Med, 2006.
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HIV-1 superinfection can occur

• Despite strong CTL, patients can be infected by a
  second strain of HIV-1

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But perhaps at a low frequency (ie infection
gives some protection)
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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 dont 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

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Innate immunity, mucosal immunity, etc
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Neutra M. NRI, 2006.
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Genital/mucosal protective factors

• Genital tract repels gt99 of HIV exposures
• Combination of factors
• Intact epithelium
• Mucus, pH, SLPI, lactoferrin, Trappin-2, etc
• ?Adaptive mucosal immunity
• Lack of co-infections also important

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What are the major genital HIV targets?
Hladik F. Immunity, 2007.
Haase A. Nat Imm Rev, 2005.
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Generating mucosal immunity
Holmgren. Nat Med, 2005.
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Immune correlates of HIV protection high risk
Kenyan sex workers
Hirbod et al. Submitted, 2007.
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Cutting edge results MC and HIV risk

• 3 large RCTs in SSA now show clear benefit
• Efficacy ITT 55, OTA 63

Viewpoint. Coates T, et al. Lancet, 2007.
Bailey et al. Lancet, 2007.
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Penile HIV target cells
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The Herpes-HIV connection
Freeman E, et al. AIDS. 200673.
Wald A. Herpes, 2004.
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Genital herpes increases HIV target cells

• These associations were seen in HSV women in the
  absence of HSV DNA shedding or clinically
  apparent ulceration

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and genital/blood HIV levels
Nagot et al. NEJM, 2007.
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GI tract may be key to HIV pathogenesis
Brenchley et al. J Exp Med, 2004.
Brenchley et al. Nat Med, 2006.
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Other innate protection

• Innate mucosal proteins
• Trappin-2, RANTES increased resistant FGT
• APOBEC3G
• Host cytidine deaminase
• Deaminates dC?dU on ss-cDNA, then get G?A on next
  strand, mutational death
• Vif targets APOBEC for proteosomal degradation
• TRIM5a
• Species-specific protection against retroviruses
• Sooty mangabey model
• Infected by SIVSM (HIV2) - high VL, high CD4
• ? via lack of immune activation, low CTL, high
  Tregs

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TRIM-5 alpha mechanism
Emerson M. PNAS, 2006.
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Summary

• No good model of active immunity to HIV
• Cellular responses are primarily responsible for
  (inadequate) control post-infection
• Antibody responses against specific epitopes may
  provide passive protection - how make active
  system?
• Innate important in transmission, ?? in control
  after infection - possible innate vaccine /
  microbicide?
• Treatment of co-infections, circumcision are
  effective immune therapies

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Discussion of paper

• Kiepiela P et al
• CD8 T-cell responses to different HIV proteins
  have discordant associations with viral load
• Nature Medicine, 2007