Identification of the Initial Targets of Transmission

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Program Director/Principal Investigator (Last, First, Middle): Hope, Thomas J. Recent advances in HIV Prevention science include the demonstration of PreP efficacy of the long acting injectable Cabotegravir and broadly neutralizing antibodies against sensitive strains. Likewise, there have been advances in HIV vaccine science with novel immunogens, adjuvants, and delivery strategies that are increasing the immune responses to the virus and their ability to prevent systemic infection. However, the fine tuning of these preventative interventions and our ability to increase their potency require a better understanding of the mechanisms of HIV sexual transmission. The primary focus of this project has been on 1) developing and optimizing methods allowing the identification of the first cells infected after a mucosal challenge; 2) the characterization of the expanding foci of infection, and 3) the definition of the cascade of events that takes place during the eclipse phase as the virus disseminates before detectable viremia. This project has uniquely impacted and advanced our understanding of the detailed natural history of the virus in the first 4 days after mucosal challenge. This success is a consequence of the innovative approach of beacon-guided necropsy where a signal is generated by the presence of infected cells. The first version of this technique utilized luciferase expressed by a replication defective dual-reporter vector. However, we have developed the next generation of this approach, which uses 64Cu labeled FAB2 probes specific for the SIV envelope protein and PET/CT as next generation beacon-guided necropsy. This approach is highly sensitive and efficient allowing the unbiased identification of multiple foci within the same animal at the whole-body level including the characterization of the interactions of the virus with host innate and inflammatory responses. The study of small foci of infection during the eclipse phase after transmission reveals a complex crosstalk between different infected cells and local tissue environment, which can vary in different areas and tissues within the same animal. This and other observations reveal target cell susceptibility, rather than the “tropism” of the viral envelope, is the key driver of early infection. It is clear that the local anatomy and physiology of virus exposed mucosal tissue has a major impact on the natural history of the virus during the eclipse phase. Through the interrogation of small tissue blocks containing replication foci, we will define the who, where, and when of early mucosal infection, including which cells are generating virus specific alarms and which cells are responding to these alarms. This will be accomplished by incorporating new approaches for the identification of cells migrating into the infected tissue site, restriction of cell mobilization, the disruption of pathways involved in innate and inflammatory responses, and short and long term responses within the infected tissues. Advancing the goals and focus of this project will result in a substantial increase in our understanding of the earliest cascade events in vaginal and rectal transmission. In turn, clarifying this process, and the impact of local anatomy and physiology on virus expansion and dissemination, will clearly advance HIV prevention science. RELEVANCE (See instructions): Developing interventions to prevent HIV infections requires a more complete understanding of how transmission is initiated and progresses to cause systemic infection. The studies proposed here will leverage state-of-the-art methodologies that can identify foci of viral replication that can be defined and characterized to guide optimization of HIV prevention approaches.