Identification of SIV replication and reservoirs in the CNS

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Abstract Even though highly potent antiretroviral therapy (ART) has the ability to reduce viral replication to undetectable levels in the plasma in simian immunodeficiency virus (SIV) infected monkeys, our recently developed viral env directed immunoPET/CT imaging technology has been able to detect foyers of continued SIV signals even after prolonged ART. However, the ability of this non-invasive technique to map SIV signal in the CNS have thus far been elusive. In this application we propose to focus on the development of probes and strategies to specifically address SIV signals in the CNS, by optimizing the technology to enable SIV specific PET probes to cross the blood brain barrier and mark cells expressing SIV env in vivo. Towards this goal we will use the pigtailed macaque model infected with SIVsmB670/SIVmac239-17E-Fred developed and validated by the team of Dr. Clements as one of the most reliable models of neuroHIV. Leveraging the strength and technological advances available at the New Iberia Research Center and Georgia Tech, we will map the seeding of reservoirs in the CNS during acute infection and monitor the kinetic of viral signals post-acute infection using a combination of immunoPET/CT, light-sheet and confocal imaging techniques, as well as sorting of infected cells to document the nature and function of cells remaining active in the early chronic phase of CNS SIV infection. Next we will document the dynamics of viral kinetics in the CNS relative to total body upon ART initiation, as well as post- ART interruption. Data generated from these highly detailed analyses will delineate which cells retain persistent viral replication under ART (if any) and more importantly evaluate the contribution of CNS viral reservoirs to the early viral rebound in vivo. The in depth analysis of this data will also provide important steps towards the development of cure strategies that include the CNS.