This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Development of an HIV-inhibiting microbicide is a priority. Consensus exists that an effective microbicide may be feasible. Simian AIDS models can help guide the development and prioritization of HIV prevention strategies. However, current models may not provide realistic pre-clinical tests of HIV prevention efficacy. The viral inoculum sizes used to infect macaques exceed those that humans are exposed to, and may underestimate the efficacy of HIV preventions. The small inocula associated with most human HIV exposures, combined with the likely stochastic nature of early infection events, may even make HIV transmission particularly susceptible to intervention. This proposal brings together investigators with expertise in AIDS virology and immunology, simian AIDS model development, and the mathematical analysis of HIV transmission events, to develop a challenge model that better recapitulates HIV transmission. The model uses vaginal inoculation with low doses of a CCR5-utilizing SHIV. Overall hypotheses: 1) Low-dose inocula, applied repeatedly, will achieve experimental SHIV infection with enough reproducibility so that prevention efficacy studies could be performed; power analyses predict that the animal numbers required to demonstrate efficacy are similar to those used in current high-dose challenge models, and 2) A low-dose challenge model will provide a more sensitive, physiologically relevant measure of the efficacy of microbicides, vaccines or other preventions. Efficacy would be demonstrated by showing that an intervention increases the number of challenges required to achieve infection, compared to controls.
Aims : 1) Characterize the dose-infectivity curve for vaginal SHIV-SF162P inoculation of pigtailed macaques, and estimate the animal infectious dose 50% (ID50), 2) Determine whether repeated challenge with the ID50 results in reproducible SHIV infection, and look for evidence that prior subinfectious exposures alter the likelihood of infection upon subsequent exposures, and 3) Analyze determinants of variable host susceptibility to vaginal infection.
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