Citation Information

Joy, J., Gervassi, A.L., Chen, L., Kirshenbaum, B., Styrchak, S., Ko, D., Mclaughlin, S., Shao, D., Kosmider, E., Edlefsen, P.T., Maenza, J., Collier, A.C., Mullins, J.I., Horton, H., and Frenkel, L.M.(2024).Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation J. Clin. Invest. 2024 Jun 4:e159569(pubmed) (doi)

Abstract

Despite effective antiretroviral therapy (ART), persons living with HIV (PWH) harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute-ART-initiators would be integrated into antiviral genes, whereas integration sites in chronic-ART-initiators would favor genes associated with cell proliferation and exhaustion. We found the HIV DNA distribution across HIV-specific vs. herpesvirus-specific CD4+ T cells was as hypothesized. HIV integration sites (IS) in acute-ART-initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1aplha-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. IS in chronic-ART-initiators were enriched in a gene set controlling EZH2 histone methylation; and methylation has been associated with diminished LTR transcription. These differences we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.