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AIDS. 2018 Jul 17;32(11):1491-1497. doi: 10.1097/QAD.0000000000001849.

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency.

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The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria.
Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Melanoma Institute Australia.
Department of Immunology, Royal Prince Alfred Hospital and the University of Sydney.
Centre for Virus Research, Westmead Millennium Institute.
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal.
Department of Microbiology, Infectiology and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Québec, Canada.
Case Western University, Cleveland, Ohio, USA.
Department of Infectious Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia.



In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T cells expressing immune checkpoint molecules, in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo.


HIV latency was established in vitro following coculture of resting CD4 T cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1 and PD-1 nonproliferating CD4 memory T cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to cocultures before and after infection. In addition, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated HIV DNA and RNA, and plasma HIV RNA were quantified.


HIV latency was significantly enriched in PD-1 compared with PD-1 nonproliferating, CD4 memory T cells. Sorting for an additional immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain-3, in combination with PD-1, further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n = 6). The administration of anti-PD-1 to an HIV-infected individual on ART resulted in a significant increase in cell-associated HIV RNA in CD4 T cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency.


PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other immune checkpoint molecules, to reverse latency.

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