Hypothesis: Multiple exposures to HIV during chemoprophylaxis will induce specific immunity. Preliminary Data: In an ongoing study we are evaluating the hypothesis that multiple viral exposures during PMPA chemoprophylaxis will induce resistance to infection after the antiretroviral chemoprophylaxis is stopped. Four experimental animals appear SIV uninfected after receiving ten weekly intravaginal inoculation of 10^4 TCID of SIVmne grown in autologous lymphocytes during daily or interrupted PMPA chemoprophylaxis. Six weeks after the PMPA was stopped all three of four appear to have resisted infection when challenged intravaginally with ten animal infectious doses of SIVMne, and subsequently two of the three were protected from a challenge of 50 animal infectious doses given on two successive days. These data suggest induction of partial or complete immune protection. This strategy induced intravaginal and serum anti-SIV antibodies, however, cellular immune responses have not yet been evaluated. Study design: To evaluate whether human infants could be immunized by this strategy we propose a pilot study of specimens collected as part of a protocol defining the pharmacokinetics of nevirapine chemoprophylaxis during birth and breastfeeding (HIVNET 023). The level of HIV-1 exposure to each infant will be estimated by determining maternal viral loads in plasma at delivery and 24 weeks postpartum and breast milk during nursing. We will determine if HIV-1 specific antibody and cellular immune responses occur more commonly in infants with a high level of viral exposure compared to those with a low level of exposure. This study of infants will not provide information as to whether infants' immune responses offer protection from infection after the discontinuation of nevirapine because the infants will be weaned. An association of immune responses with exposure to high levels of HIV-1 during birth and in breast milk, however, would support the concept that mucosal immunization of infants is possible. If a correlation of HIV-1 specific immune responses with exposure to virus during chemoprophylaxis is observed in this pilot study an additional study comparing the infection rate of a large number after chemoprophylaxis of breastfeeding to of infants to breastfed infants who do not have a period of chemoprophylaxis. Relevance: To ascertain whether HIV-1 chemoprophylaxis during viral exposures is effective in evoking an anti-HIV-1 immune response is urgent, because if an immune response is evoked, it could lead to partial or complete protection from infection. While disease attenuation falls short of the goal of immunization, it may result in long-term health benefits to the individual and slow the rate of transmission in a community. Importantly, if this strategy proves effective as the preliminary data suggests, this would provide the basis for a vaccine strategy incorporating antiviral prophylaxis, or entry competent but integration deficient virus. In the absence of an effective vaccine, the use of antiretrovirals should be optimized to prevent the spread of HIV-1 infection. This proposal works toward this goal.
