I-105 Nonhuman primate models in the study of early events in AIDS virus infection

Abstract

Nonhuman primate (NHP) models have proven invaluable for the detailed study of many aspects of AIDS virus pathogenesis difficult or impossible to study with comparable rigor in HIV infected humans. Key aspects of HIV infection in humans can be authentically recapitulated in NHP models. Experimental advantages of NHP models include the ability to exactly control the identity, dose, route, and timing of the viral inoculum employed, control over the timing of initiation and discontinuation of various experimental interventions and the ability to conduct in vivo proof of concept studies of promising but unproven and potentially dangerous treatments. As AIDS virus infection is a tissue based disease, perhaps the most important advantage of NHP models is the ability to obtain extensive longitudinal tissue samples, including from scheduled euthanasia and necropsy with extensive tissue collection and analysis. Early events in the course of AIDS virus infection are critically important, but difficult to study in HIV infected humans, due to factors that often include delayed diagnosis, and uncertainty about the exact timing of exposure, along with lack of availability of informative tissue specimens. NHP models therefore have an important role to play in the study of early events in AIDS virus infection. Using examples from our recent studies, results will be presented in a series of vignettes demonstrating the utility of NHP models for the study of early events in infection, including: (1) the use of a sequence tagged viral inoculum for tracking independent chains of infection events in vivo involved in mucosal viral transmission and systemic dissemination of infection; (2) the impact of early implementation of combination antiretroviral drug treatment (cART) on limiting the extent of establishment of a durable, recrudescence competent viral reservoir; (3) the contribution of arrest of viral replication at distal sites, after initial dissemination from a mucosal portal of entry, to protection from infection mediated by broadly neutralizing monoclonal antibodies; and iv. the early establishment of expanded clones of CD4+ T cells harboring clonally integrated proviruses that may contribute to the recrudescence competent viral reservoir that persists during cART.