Summary
Despite the development of potent anti-retroviral therapy (ART) that successfully suppresses virus replication in
the majority of people living with HIV (PLWH), there is no treatment that can cure this infection entirely. The
major obstacle in eradicating HIV is the persistence of various anatomical viral reservoirs (VRs), including the
central nervous system (CNS), that have the capacity to produce infectious virus and systemically spread within
a short period upon cessation of ART in all, with few exceptional cases. Therefore, developing novel interventions
aimed at reducing or eliminating the VRs is one of the key priorities for HIV research. In response to RFA-MH-
20-701, our application proposes basic science and preclinical research in SIV-infected rhesus macaques (RMs)
to model aspects of VR in the CNS-resident myeloid cells of PLWH, and to investigate the efficacy of the novel
pharmacologic strategy to prevent establishment of HIV persistence in the CNS. Thus, based on the
observations outlined in this application we hypothesize that the disruption of PMC formation during acute phase
of infection will limit the seeding and maintenance of VR and, as a consequence, the extent of viral rebound in
the CNS following analytical therapy interruption (ATI). Three aims are proposed: (1) To investigate whether the
systemic disruption of PMC formation during acute phase of infection, regulates viral persistence in the CNS; (2)
To investigate whether the systemic disruption of PMC formation during acute phase of infection, regulates the
kinetics and extent of viral rebound after ATI; and (3) To investigate whether the systemic disruption of PMC
formation during acute phase of infection, regulates the neuroinflammation and synaptodendritic damages
associated with long-term ART and ATI. These aims will be achieved by (i) using a well-established model of
SIV-infected RMs treated with suppressive ART, and (ii) performing in vivo Ab-mediated disruption of PMC
formation during acute phase of untreated infection. Revealing the mechanisms through which platelets regulate
the persistence of HIV in myeloid cells will provide a critical understanding of how these cellular interactions
function in mammalian cells, and an insight into how a potential HIV cure can be achieved in PLWH.
