Although patients on successful combination antiretroviral therapy (cART) show sustained viral suppression in the cerebrospinal fluid (CSF) as well as plasma, ?blips? indicative of transient HIV replication are often found with more frequent CSF testing. Recent studies link persistent immune activation, neuroinflammation, and CSF viral escape in cART-treated individuals to increased disease progression, as well as an increased risk for HAND. In this application, it is proposed that in patients on optimal cART, HAND is driven by recall immune responses to small amounts of antigen produced during this transient CSF viral escape. Over the previous funding period of this grant, we have described a population of CD8(+)CD103(+)CD127(+) memory T-cells which remain as permanent residents within the brain following viral infection. Building on these findings, we used a heterologous prime-boost strategy in which mice are immunized with recombinant adenovirus vectors expressing the HIV-1 p24 capsid protein (rAd5-p24), followed by a CNS boost using Pr55Gag/Env virus-like particles (HIVLPs). This approach allowed us to develop an innovative experimental model in which the murine brain becomes populated by resident CD8(+) memory T-cells specific for immunodominant HIV-1 Gag epitopes. In addition, subsequent anti-HIV-1 recall responses can then be induced in response to stimulation using defined peptide epitopes. This novel approach allows us to investigate the neuroimmune pathogenesis of recall immune responses in a powerful, yet convenient and inexpensive small animal model. Despite its importance to understanding and treating HAND, nothing is currently know about how anti-HIV-1 recall responses from brain-resident memory CD8(+) T-cells (bTRM) trigger tissue-wide innate immune responses which drive reactive gliosis-mediated neurotoxicity. Experiments proposed in this application will fill this gap in knowledge. The central hypothesis to be tested is that adaptive, anti-HIV-1 recall responses from bTRM trigger tissue-wide innate immune responses from reactive glia that promote inflammation-induced synaptic damage, neurotoxicity, and long-term neurocognitive impairment. The studies will first determine whether anti-HIV-1 recall responses from CD8(+)CD103(+)CD127(+) bTRM induce reactive gliosis and trigger broad innate neuroinflammatory responses. Experiments proposed in Aim #2 will go on to determine whether these anti- HIV-1 recall responses trigger synaptodendritic damage, neurotoxicity, and long-term neurological sequelae. Finally in Specific Aim #3, which is more translational, we will determine whether anti-HIV-1 recall response- driven neuroinflammation can be ameliorated through immunomodulatory approaches. Although patients on successful cART show sustained viral suppression, antiviral treatment alone does not fully protect against neurocognitive impairment. Still, partial protection by cART does indicate a direct connection to HIV replication. For these reasons, immunomodulation of neurotoxic, recall response-driven neuroinflammation in response to CSF viral escape is clearly a promising adjunctive approach to mitigating neural damage.
HIV-associated neurocognitive disorders (HAND) persist even during successful combination antiretroviral therapy (cART) when viral loads in the cerebrospinal fluid (CSF), as well as plasma, are below detectable limits. Studies presented in this application address the question of what drives neural damage and the resulting cognitive deficits in the absence of a detectable viral load. Recent studies link CSF viral escape, persistent immune activation, and chronic neuroinflammation to an increased risk for HAND; for this reason, immunomodulation of neurotoxic, recall response-driven inflammation in response to CSF viral escape is clearly a promising adjunctive therapy in mitigating neural damage seen during HAND.
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