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-1high and PD-1low/− 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-1high compared with PD-1low/- 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.
aThe Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria
bChris O’Brien Lifehouse, Royal Prince Alfred Hospital, Melanoma Institute Australia
cDepartment of Immunology, Royal Prince Alfred Hospital and the University of Sydney
dCentre for Virus Research, Westmead Millennium Institute
eSydney Medical School, University of Sydney, Sydney, New South Wales, Australia
fCentre de Recherche du Centre Hospitalier de l’Université de Montréal
gDepartment of Microbiology, Infectiology and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Québec, Canada
hCase Western University, Cleveland, Ohio, USA
iDepartment of Infectious Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia.
Correspondence to Professor Sharon R. Lewin, FRACP, PhD, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne 3000, VIC, Australia. Tel: +61 3 8344 3159; fax: +61 3 9347 2952; e-mail: email@example.com
Received 23 January, 2018
Revised 14 March, 2018
Accepted 28 March, 2018
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