Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites.

Autor: Lee E; The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia eunok.lee@sydney.edu.au., von Stockenstrom S; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Morcilla V; The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia., Odevall L; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Hiener B; The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia., Shao W; Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Hartogensis W; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Bacchetti P; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA., Milush J; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Liegler T; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Sinclair E; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Hatano H; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Hoh R; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Somsouk M; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Hunt P; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Boritz E; Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Douek D; Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Fromentin R; Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Canada., Chomont N; Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Canada., Deeks SG; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Hecht FM; Department of Medicine, University of California San Francisco, San Francisco, California, USA., Palmer S; The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Journal of virology [J Virol] 2020 Jan 17; Vol. 94 (3). Date of Electronic Publication: 2020 Jan 17 (Print Publication: 2020).
DOI: 10.1128/JVI.01270-19
Abstrakt: Understanding the impact of antiretroviral therapy (ART) duration on HIV-infected cells is critical for developing successful curative strategies. To address this issue, we conducted a cross-sectional/inter-participant genetic characterization of HIV-1 RNA from pre- and on-therapy plasmas and HIV-1 DNA from CD4 + T cell subsets derived from peripheral blood (PB), lymph node (LN), and gut tissues of 26 participants after 3 to 17.8 years of ART. Our studies revealed in four acute/early participants who had paired PB and LN samples a substantial reduction in the proportion of HIV-infected cells per year on therapy within the LN. Extrapolation to all 12 acute/early participants estimated a much smaller reduction in the proportion of HIV-1-infected cells within LNs per year on therapy that was similar to that in the participants treated during chronic infection. LN-derived effector memory T (T EM ) cells contained HIV-1 DNA that was genetically identical to viral sequences derived from pre- and on-therapy plasma samples. The proportion of identical HIV-1 DNA sequences increased within PB-derived T EM cells. However, the infection frequency of T EM cells in PB was stable, indicating that cellular proliferation that compensates for T cell loss over time contributes to HIV-1 persistence. This study suggests that ART reduces HIV-infected T cells and that clonal expansion of HIV-infected cells maintains viral persistence. Importantly, LN-derived T EM cells are a probable source of HIV-1 genomes capable of producing infectious HIV-1 and should be targeted by future curative strategies. IMPORTANCE HIV-1 persists as an integrated genome in CD4 + memory T cells during effective therapy, and cessation of current treatments results in resumption of viral replication. To date, the impact of antiretroviral therapy duration on HIV-infected CD4 + T cells and the mechanisms of viral persistence in different anatomic sites is not clearly elucidated. In the current study, we found that treatment duration was associated with a reduction in HIV-infected T cells. Our genetic analyses revealed that CD4 + effector memory T (T EM ) cells derived from the lymph node appeared to contain provirus that was genetically identical to plasma-derived virions. Moreover, we found that cellular proliferation counterbalanced the decay of HIV-infected cells throughout therapy. The contribution of cellular proliferation to viral persistence is particularly significant in T EM cells. Our study emphasizes the importance of HIV-1 intervention and provides new insights into the location of memory T cells infected with HIV-1 DNA, which is capable of contributing to viremia.
(Copyright © 2020 Lee et al.)
Databáze: MEDLINE
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