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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.02214

Memory CD4+ T-cells expressing HLA-DR contribute to HIV persistence during prolonged antiretroviral therapy

 Eunok Lee1, 2*, Peter Bacchetti3, Jeffrey Milush4,  Wei Shao5, Eli Boritz6, Daniel Douek6,  Remi Fromentin7, Teri Liegler4,  Rebecca Hoh4,  Steven G. Deeks4, Frederick Hecht4,  Nicolas Chomont7 and Sarah Palmer1, 2
  • 1Centre for Virus Research, Westmead Institute for Medical Research, Australia
  • 2Sydney Medical School, University of Sydney, Australia
  • 3Department of Epidemiology and Biostatistics, University of California San Francisco, United States
  • 4School of Medicine, University of California San Francisco, United States
  • 5Frederick National Laboratory for Cancer Research (NIH), United States
  • 6National Institute of Allergy and Infectious Diseases (NIAID), United States
  • 7Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, University of Montreal, Canada

To date, most assays for measuring the human immunodeficiency virus (HIV-1) reservoir do not include memory CD4+ T-cells expressing the activation marker, human leukocyte antigen-antigen D related (HLA-DR). However, little is known concerning the role these cells play in maintaining persistent HIV-1 during effective antiretroviral therapy (ART). To address this issue, we examined, cellular activation/exhaustion markers (Ki67, CCR5, PD-1, Lag-3 and Tim-3) and viral gag-pol DNA sequences within HLA-DR- and HLA-DR+ memory CD4+ T-cell subsets longitudinally from the peripheral blood of six participants over 3 to ≥15 years of effective therapy. HLA-DR expression was readily detected during the study period in all participants. The average expression levels of CCR5, PD-1 and Tim-3 were higher on the HLA-DR+ T-cell subset whereas the average of LAG-3 expression was higher on their HLA-DR- counterpart. The proportion of HIV-infected cells increased within the HLA-DR+ subset by an average of 18% per year of ART whereas the frequency of infected HLA-DR- T-cells slightly decreased over time (5% per year). We observed that 20-33% of HIV-DNA sequences from the early time points were genetically identical to viral sequences from the last time point within the same cell subset during ART. This indicates that a fraction of proviruses persists within HLA-DR+ and HLA-DR- T-cell subsets during prolonged ART. Our HIV-DNA sequence analyses also revealed that cells transitioned between the HLA-DR+ and HLA-DR- phenotypes. The Ki67 expression, a marker for cellular proliferation, and the combined markers of Ki67/PD-1 averaged 19-fold and 22-fold higher on the HLA-DR+ T-cell subset compared to their HLA-DR- counterpart. Moreover, cellular proliferation, as reflected by the proportion of genetically identical HIV-DNA sequences, increased within both T-cell subsets over the study period; however, this increase was greater within the HLA-DR+ T-cells. Our research revealed that cellular transition and proliferation contribute to the persistence of HIV in HLA-DR+ and HLA-DR- T-cell subsets during prolonged therapy. As such, the HIV reservoir expands during effective ART when both the HLA-DR+ and HLA-DR- cell subsets are included, and therapeutic interventions aimed at reducing the HIV-1 reservoir should target HLA-DR+ and HLA-DR- T-cells.

Keywords: HLA-DR, CD4+ T-cells, prolonged ART, HIV persistence, cell activation/exhaustion markers, cellular proliferation, single-proviral sequencing

Received: 13 Jul 2019; Accepted: 10 Sep 2019.

Copyright: © 2019 Lee, Bacchetti, Milush, Shao, Boritz, Douek, Fromentin, Liegler, Hoh, Deeks, Hecht, Chomont and Palmer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Ms. Eunok Lee, Centre for Virus Research, Westmead Institute for Medical Research, Sydney, 2145, Australia,