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

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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. Overall, this award is integral to the completion of these aims in understanding the foundation of the mechanistic, basic science behind antibody distribution and localization events. With this opportunity, combined with the mentorship provided by Dr. Thomas Hope and Dr. Ronald Veazey, I can start to unravel the complexities of how protective antibodies are delivered to those sites involved in HIV transmission and pathogenesis. This knowledge is critical to advance the effort in the development of a vaccine that is able to provide protection from HIV infection, especially at mucosal sites. Additionally, the training opportunities to elucidate these mechanisms are extremely valuable to my development as a researcher, as it will also provide me with an important skillset and future experimentation that I can carry forward to academic independence.