1. ANIMAL MODELS FOR HIV VACCINES Girish N. Vyas, Ph.D. UCSF School of Medicine, San Francisco (UCSF) A quote from the keynote Address at the January, 2008 Congress of the Intl Soc Cell and Gene Therapy applicable to HIV Vaccine? “Mice tell lies and monkeys do not tell the truth. Human clinical trials alone provide the proof” WEAA03 Session, Aug 6, ‘08, International AIDS Conference, Mexico City

2. Live AttenuatedWhole inactivated HIV peptide Recombinant protein subunit DNA Live virus vector Live bacterial vector

3. PREMISE FOR AN HIV VACCINE MODEL Vaccines are aimed at producing a potent antibody response protective against a pathogen without producing an infection. Lessons learnt from HBsAg vaccine against HBV appear applicable to fruitful HIV vaccine development. Antibody response in HIV-infected persons has more than 10 distinct specificities to HIV-gp 41/120 but together they fail to protect against HIV-1 infection. Essential to elicit antibody response broader than that in HIV-1 infected persons. For effective protection a vaccine must induce antibody response to both envelope proteins, HIV-gp41 and -120. Monoclonal antigens/antibodies have apparently proven inadequate. Genetic diversity of population-prevalent HIV-1 may be necessary for developing an effective polyvalent HIV vaccine

4. Geographic Distribution of HIV-1 Subtypes Most Animal Work Done with HIV-1 Subtype B B,A,D,E B, E, F,C B,A,C,D,E,F,G,H A,C,D, E,F,G,H B E,B C,B,E Adapted from U.S. Military HIV Research Program

5. ANIMAL MODELS USEFUL IN HIV VACCINE R&D NONHUMAN PRIMATES (NHP) Chimpanzee: Useful model for HIV-1 infection and immunity but not pathogenesis; expensive and available with difficulty. Macaques: SIV and SHIV, a chimeric analogue of HIV, used as model for immunization/challenge. Baboons: Though not susceptible to infection with HIV-1, it is a useful nonhuman primate model for phylogenetically relevant anti-HIV response. SMALL ANIMALS SCID-hu mouse: A heterochimeric small animal model improved upon by hollow-fiber SCID model used for evaluation of antivirals. Intrathymic injection of 4XTCID-50 infected 15/16 animals (Stoddard, personal communication, August 2008) Cats: Vaccine against Feline Immunodeficiency Virus (FIV) may provide a biological paradigm.

6. Non-human Primate Models for AIDS Vaccine Research Critical component of AIDS vaccine research effort for foreseeable future Discovery and applied evaluation Proof of concept prior to efficacy testing (exceptions) Resources, infrastructure inadequate to expanding demands

7. Non-human Primate Models for AIDS Vaccine Research Multiple models available; none perfect Model = NHP species, challenge virus, route/dose, predictable outcome Viruses in vivo adapted/selected Match model to research question

8. Non-human Primate Models for AIDS Vaccine Research Standardization Comparative evaluation of vaccine candidates Model(s) Challenge stocks (homolog, heterolog) Laboratory analysis (virology, immunology) Two edged sword absent “perfect” model Dangers of standardization for its own sake Match model to research question

9. Non-human Primate Models for AIDS Vaccine Research New model development Other SIVs (breadth, heterolog, in vivo) R5 SHIVs Minimally chimeric HIV-1’s In vivo manipulations

10. Attenuated SIV Strains SIVmac239 ∆nef SIVmac239∆3 SIVmac239∆4 Marie-Claire Gauduin, Ph.D.

11. 10 3 0 10 1 10 2 10 4 10 5 10 6 10 7 10 8 Wild-type SIV Live, attenuated strains  nef  3 (  nef,  vpr,  US)  4 (  nef,  vpr,  vpx,  US) Duration of infection SIV Plasma RNA (copies/ml) Limit of Detection Adapted from R. Desrosiers et al. Replication of Attenuated SIV in Vivo

12. Summary of Scientific Issues and Questions Trial designs Laboratory Methods Sterilizing immunity vs disease modulation? Viral Diversity/ Different Clades HIV pathogenesis (latency) and virus immune escape mechanisms Correlates of immunity Neutralizing ab vs CTL or both What are the best strategies to achieve both? Vaccine designs to generate broad neutralizing ab to circulating strains (primary) isolates Animal models: Lack of good models and understanding of mechanisms of protection