Understanding the mechanism(s) of systemic antibody delivery, distribution, and localization to mucosal sites in the in vivo macaque model

To date, although the number HIV-related deaths are on the decline due to antiretroviral and other biomedical interventions, there is still a vaccine lacking for HIV. Recently, there has been increased interest in the utilization of broadly neutralizing antibodies (bNAbs) as a vaccine strategy, which have been illustrated to bind and inactivate lentiviral particles in non-human primate models. Not only have bNAb passive transfer studies in rhesus macaques demonstrated protection against lentiviral infection, but have also led to the first bNAb human clinical trial, the Antibody Mediated Protection (AMP) study. Although these are valiant efforts towards blocking HIV infection, it is still unknown how these antibodies are delivered to mucosal sites where HIV transmission occurs. Gaining a better understanding of how these antibodies are anatomically distributed will have a great impact in the effort to develop a vaccine to prevent HIV acquisition. In order to accomplish this objective, I have been working to develop a novel platform to track fluorescently labeled antibodies in the in vivo rhesus macaque model. To date, utilizing this technique, I have revealed that antibodies take approximately one week to reach a steady state after infusion — an observation that could have implications for the ongoing AMP trial. Additionally, I have observed unique bNAb localization within tissue resident cells in those areas important in HIV transmission and pathogenesis, such as the rectal and vaginal mucosa, and brain. Based on these preliminary data, I propose in Aim 1 to identify the mechanisms of antibody transport and localization using the in vivo nonhuman primate model. In Aim 2, I will characterize the mechanism(s) of antibody association with specific, tissue resident cells at distinct anatomical sites after systemic application. Finally, in Aim 3, I will use the data from the first two aims to determine if antibody subclass influences tissue transport and localization.