HIV infection of the CNS persists despite antiretroviral treatment, representing a challenge for treatment of neurologic disorders and a significant hurdle for the eradication of HIV in treated patients. It is likely that elimination ofHIV infected reservoirs in the brain will require interventions designed to stimulate immune recognition of HIV infected cells and/or circumvent immune suppressive mechanisms. Adenosine triphosphate (ATP) is a potent immune stimulant, acting via P2-type receptors on immune cells. Adenosine, in contrast, has potent immune suppressive activities on T cells and macrophages/dendritic cells via P1-type receptors. Microglia in CNS, similar to an action of regulatory T cells, express ectonucleotidases CD39 and CD73, which convert ATP and ADP to AMP (via CD39), with further metabolism to adenosine (via CD73), providing a potentially important mechanism mediating immune modulation. In our preliminary studies in CNS tissues from SIV infected rhesus macaques, both CD39 and CD73 exhibit increased expression relative to uninfected control brain tissue. The expression of both ectoenzymes is markedly increased on parenchymal microglia in SIV infected brain, even in the absence of encephalitis. In addition, CNS perivascular macrophages and cells within microglial nodules, highly express these enzymes in the setting of SIV encephalitis In our proposed studies, we will test the hypothesis that ATP metabolism, via the enzymatic activities of CD39 and CD73 expression on microglia, is increased in the CNS in SIV infected rhesus macaques, contributes to the survival of infected cells, and impairs virus specific immune responses.
In Specific Aim I, we will test the hypothesis that CD39 and CD73 expression on microglia, is increased in SIV infection and determine the impact of cART treatment on expression and enzymatic activity. We will further evaluate ATP metabolites as biomarkers in CSF during the course of this study and determine if values correlate with SIV infection status, biologic and virologic markers for pathogenesis, CD39 and CD73 expression in CNS, and the response to cART treatment. We will test the hypothesis increased CD39 and CD73 expressed on brain derived microglia in SIV infection contributes to ATP metabolism, suppresses T cell responses, and increase survival of microglia in vitro. We will measure and compare ectonucleotidase activities, the ability to suppress autologous SIV specific immune responses, and the sensitivity to ATP induced cell death, using CNS derived microglia from uninfected controls, SIV infected, and SIV infected rhesus macaques treated with cART. We anticipate that our proposed studies will provide a novel avenue for therapeutics to augment immune mediated clearance of HIV and other CNS pathogens.
HIV infection is a devastating disease showing important neurological impairments, with the brain being a location resistant viral clearance by antiviral drugs. The studies proposed here may promote new therapeutic approaches toward clearing reservoirs of infection that are resistant to current treatments.
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