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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.

Author information

1
The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria.
2
Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Melanoma Institute Australia.
3
Department of Immunology, Royal Prince Alfred Hospital and the University of Sydney.
4
Centre for Virus Research, Westmead Millennium Institute.
5
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
6
Centre de Recherche du Centre Hospitalier de l'Université de Montréal.
7
Department of Microbiology, Infectiology and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Québec, Canada.
8
Case Western University, Cleveland, Ohio, USA.
9
Department of Infectious Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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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