Learning from studies of HEPS individuals: are they the HIV equivalent of Jenners milkmaids

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Learning from studies of HEPS individuals are
they the HIV equivalent of Jenners milkmaids?

• Dr. Rupert Kaul
• University of Toronto

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Edward Jenner (1749-1823)

• Small pox mortality 30
• Partial protection by variolation (1-2
  mortality)
• Hypothesized that cow pox (variola vaccinae)
  protective
• Took discharge from cow pox on hand of Sarah
  Nelmes (Blossom) and inoculated James Phipps (8
  yr)
• Variolation or smallpox exposure ? no clinical
  effect

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Highly Exposed, Persistently Seronegative (HEPS)

• Individuals remaining apparently HIV uninfected
  despite substantial exposure
• Spectrum of exposure
• Exact definitions vary
• NB sexual transmission probability lt1
• Variable circumstances for exposure
• Sex workers (M/F) MSM with many partners IVDU
  discordant couples HCWs

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What can the study of HEPS teach us?

• That relative HIV resistance is possible
• Fundamental aspects of HIV biology
• CCR5 (Paxton, Nat Med 1996 ? Liu, Cell 1996
  Huang, Nat Med 1996)
• CORRELATES of reduced HIV susceptibility in the
  most relevant biological model
• Immune correlates - humoral, cellular, innate
• Genetic correlates - IRF-1 (Ji, MOAX0103)
• Clinical/behavioural correlates

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Env-specific CTL in HEPS

• Cross sectional study
• Assays unblinded
• PROSPECTIVE
• ANALYSIS

J Clin Invest. 2001.
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Env-specific CTL and HIV acquisition

• Blinded, prospective analysis predefined assay
• CTL at baseline c/w age, increased HIV exposure
• CTL associated with protection against HIV
  acquisition
• Dropped out in multivariable model

AIDS, 2004.
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HIV-neutralizing IgA in HEPS
Again, a cross-sectional unblinded study AIDS,
2001.
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Neutralizing IgA and HIV acquisition

• Prospective, nested case control study
• Blinded assays predefined criteria
• Protection indep. associated with IgA
  neutralizing both clades A, C
• Hirbod, T. THLB0301.

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Genital innate factors in HEPS

• Identified as Trappin 2
• HIV-neutralizing activity in vitro
• Prospective studies ongoing

Iqbal S. WEAA0504.
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What can HEPS not teach us?

• CAUSE of reduced HIV susceptibility
• No challenge possible
• Exact phenotype of infecting virus unknown
• Ideally ALSO need
• development of a relevant animal model for
  preclinical vaccine / microbicide work
• Human clinical trials to demonstrate causation

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Mandate for improved HEPS studies

• Blinded lab analysis if possible
• Prospective studies - closer to causation
• Clinical / demographics important
• Attempt to elucidate strongest correlates
• Comprehensive approach
• everything on everybody
• Follow up with multivariable analysis

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Behavioural interventions HEPS
Ngugi, E. Chakkalackal, M.
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Genital coinfections and HIV susceptibility

• HIV acquisition strongly associated with HSV-2
  adjusted Cox regression RR 5.8

JAMA. 2004.
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HIV uninfected (susceptible) FSWs

• These associations were seen in HSV women in the
  absence of HSV DNA shedding or clinically
  apparent ulceration.
• Rebbapragada, A. WEAA0304.

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CONCLUSIONS

• There is no more realistic model for HIV
  susceptibility and disease than humans
• HEPS studies provide vaccine microbicide
  research with correlates of protection
• Showing causation needs preclinical animal work,
  followed by rigorous human trials
• BUT the rigor of HEPS studies can (should) be
  improved

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AcknowledgementsKaul lab Prameet Sheth, Anu
Rebbapragada, Chris Pettengel, Sanja Huibner,
Bolette Bossen, Sherzana Sunderji, Anthony
Sheung, Duncan ChegeUniversity of Nairobi
Joshua Kimani, Charles Wachihi, Job Bwayo,
Elizabeth Ngugi, Walter Jaoko many
othersUniversity of Manitoba John Rutherford,
Blake Ball, Keith Fowke, Shehzad Iqbal, Stephen
Moses, Frank PlummerGhent University Karolien
Fonck, Marleen TemmermanKarolinska Institutet
Claudia Devito, Taha Hirbod, Kristina
BrolidenUniversity of Toronto Kelly
MacDonaldPARTICIPANTS IN THE PUMWANI, KIBERA
COHORTSFunding NIH, CIHR, MRC, University of
Toronto, OHTN, Canada Research Chair
Programme, Rockefeller, amFAR, Connaught, BMGF