This grant application is submitted in response to RFA AI-94-029, """"""""Pediatric AIDS: Factors in Transmission and Pathogenesis"""""""". Study of early events in HIV infection after perinatal virus exposure of infants is especially needed for the rational design of prophylactic treatments or vaccines to prevent HIV infection by perinatal exposure as well as to develop anti-viral therapies for infected infants. Such human studies are difficult or impossible to perform because the infecting viral inocula, the route of exposure to virus, and the precise time of infection are unknown. However, the SIV/rhesus macaque model of pediatric HIV infection is ideally suited to study early events in perinatal transmission of virus because virological and host variables can be experimentally separated to test specific hypotheses. Three pieces of critical information are lacking in human studies of perinatal HIV transmission that can be easily obtained in the SIV/rhesus macaque model of HIV perinatal transmission: (1) detailed understanding of the role of viral characteristics in the infecting inoculum including the infectious titer and biological properties of viral variants, (2) timing and route of exposure to virus, and (3) the roles of immune responses and virus load on pathogenesis by detailed measures of virus levels and cell- mediated and humoral immunity, in infected neonates. Hypotheses: 1) The rate of disease progression in SIV-infected neonates is determined by the infectious dose and composition (genotype and phenotype) of the virus inoculum and the route of virus exposure, and 2) Therapies or treatments that reduce the dose of infectious virus below a minimum threshold associated with persistent viremia will delay or prevent fatal disease in SIV-infected neonatal rhesus macaques.
Three Specific Aims are proposed: 1) To determine the minimum dose of SIV that results in rapidly fatal immunodeficiency following oral and intravenous virus exposures. 2) To determine whether disease progression, immune responses or virus load differs in rhesus neonates infected with defined mixtures of pathogenic and attenuated SIV variants. 3) To prevent virus infection or disease in SIV-inoculated neonatal rhesus macaques using a topical antiviral agent or immunotherapies. The project proposed will attempt to answer fundamental questions regarding the effects of different viral variants, infectious doses of virus, and routes of virus exposure on the rate of disease progression in neonates after exposure to SIV and, by extension, HIV. The information generated by this project will be directly applicable to the design of strategies aimed at preventing HIV infection of human infants or delaying disease progression in those infants that become HIV-infected.
