Targeting cell-to-cell communication to prevent bystander damage mediated by viral reservoirs

Abstract: “Targeting cell-to-cell communication to prevent bystander damage mediated by viral reservoirs.” Soon after primary infection, HIV enters the CNS and causes long-lasting cognitive and motor impairment in 30-60% of infected individuals, even in the current antiretroviral (ART) era. In the CNS, HIV remains latent in a small population of microglia/macrophages and a smaller population of astrocytes. Our human brain data indicate that long-term ART reduces the myeloid (microglia/macrophage) pool of viral reservoirs (up to 23 years on ART). However, long-term ART did not reduce the astrocyte-infected pool. Furthermore, chronic damage to uninfected cells was associated with glial viral reservoirs and amplified by Connexin43 containing channels, gap junction (GJ) and hemichannels (HC), even in the absence of viral replication. Our application focuses on astrocytes and the mechanism of bystander damage triggered by viral reservoirs, even in the absence of replication. Overall, our data indicate: First, a small population of latently infected astrocytes remain stable even during long-term ART (up to 23 years in ART); Second, the few astrocytes with HIV-integrated DNA are associated with localized inflammatory areas; Third, HIV-infected astrocytes survive apoptosis for extended periods; Fourth, we demonstrated that few infected astrocytes could repopulate the entire body with the virus and Fifth, we demonstrated that connexin containing channels, GJ and HC, amplify chronic inflammation into neighboring uninfected cells by a mechanism involving compromised calcium/IP3 signaling, mitochondrial function, and inter-organelle interactions (ER, mitochondria and lipid bodies); and Lastly, we demonstrated all these toxic mechanisms could be prevented by reducing GJ and HC communication between viral reservoirs and surrounding uninfected cells. We hypothesize that “HIV-latently infected astrocytes used GJ and HC to amplify toxicity into neighboring uninfected cells even in the current ART era.” The results obtained from this proposal will lead to identifying potential therapeutic targets to limit the devastating consequences of NeuroHIV.