Astrocyte HIV-1 Proviral Reservoirs in HAND




Borgmann, Kathleen
Edara, Venkata Viswanadh
Ghorpade, Anuja


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Purpose: Even though astrocytes are restrictively infected with HIV-1, they are capable of producing neurotoxic viral proteins and proinflammatory mediators. This can significantly aggravate the pathogenesis of HIV-associated neurocognitive disorders (HAND). Thus, there is a great need to identify latently infected astrocytes and develop strategies to target this elusive population. We hypothesize that harboring HIV-1 proviral reservoirs alters astrocyte function in conjunction with unique gene expression patterns that could serve as biomarkers and facilitate targeted therapy. Methods: Red/Green-HIV-1 (R/G-HIV-1) was used to visualize viral promoter (LTR) activity in primary human astrocytes. Astrocytes with active (R+/G+) and silent (R+/G-) LTRs were enriched using FACS. Results: Nested Alu-gag PCR confirmed the presence of integrated R/G-HIV-1 provirus in transduced astrocytes. Astrocytes with silent promoter activity were devoid of late viral proteins such as p24, indicating a functionally silent HIV-1 LTR. However, interluekin-1β (IL-1β) and Vorinostat, a histone deacetylase inhibitor (HDACi), reactivated silent HIV-1 LTR in R/G-HIV-1+ astrocytes. Glutamate clearance ability and cell proliferation were significantly impaired in astrocytes with either silent (R+/G-) or active (R+/G+) HIV LTRs when compared to integrase deficient R/G-HIV-1 (D116A) transduced cells. Conclusions: Our data suggest that harboring HIV-1 provirus, either active or silent, interfered with astrocyte function and growth. Hence, we propose that identifying biomarkers for astrocytes harboring HIV provirus, and therapeutic gene editing to eliminate proviral gene expression will improve physiological function compared to HIV-1 infected cells.