HIV-1 Genomes Are Enriched in Memory CD4 + T-Cells with Short Half-Lives.

Autor:	Morcilla V; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia., Bacchus-Souffan C; Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA., Fisher K; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.; Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Horsburgh BA; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.; Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Hiener B; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.; Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Wang XQ; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.; Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Schlub TE; Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Fitch M; Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California, USA., Hoh R; Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA., Hecht FM; Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA., Martin JN; Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA., Deeks SG; Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA., Hellerstein MK; Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California, USA., McCune JM; Global Health Innovative Technology Solutions/HIV Frontiers, Bill & Melinda Gates Foundation, Seattle, Washington, USA., Hunt PW; Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA., Palmer S; Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.; Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2021 Oct 26; Vol. 12 (5), pp. e0244721. Date of Electronic Publication: 2021 Sep 21.
DOI:	10.1128/mBio.02447-21
Abstrakt:	Future HIV-1 curative therapies require a thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets during antiretroviral therapy (ART) and the cellular mechanisms that maintain this reservoir. Therefore, we sequenced near-full-length HIV-1 genomes and identified genetically-intact and genetically-defective genomes from resting naive, stem-cell memory, central memory, transitional memory, effector memory, and terminally-differentiated CD4 + T-cells with known cellular half-lives from 11 participants on ART. We find that a higher infection frequency with any HIV-1 genome was significantly associated with a shorter cellular half-life, such as transitional and effector memory cells. A similar enrichment of genetically-intact provirus was observed in these cells with relatively shorter half-lives. We found that effector memory and terminally-differentiated cells also had significantly higher levels of expansions of genetically-identical sequences, while only transitional and effector memory cells contained genetically-intact proviruses that were part of a cluster of identical sequences. Expansions of identical sequences were used to infer cellular proliferation from clonal expansion. Altogether, this indicates that specific cellular mechanisms such as short half-life and proliferative potential contribute to the persistence of genetically-intact HIV-1. IMPORTANCE The design of future HIV-1 curative therapies requires a more thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets as well as the cellular mechanisms that maintain this reservoir. These genetically-intact and presumably replication-competent proviruses make up the latent HIV-1 reservoir. Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them. Therefore, our study delivers an in-depth assessment of the cellular mechanisms, such as cellular proliferation and half-life, that contribute to and maintain the latent HIV-1 reservoir.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu