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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Vanessa A Evans
  • ,
  • Renée Marije van der Sluis
  • Ajantha Solomon, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Ashanti Dantanarayana, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Catriona McNeil, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Melanoma Institute Australia.
  • ,
  • Roger Garsia, Department of Immunology, Royal Prince Alfred Hospital and The University of Sydney, Sydney, Australia
  • ,
  • Sarah Palmer, 1] Department of Pain Management, Greenwich Hospital, Hammond Care, Sydney, New South Wales, Australia [2] Sydney Medical School-Northern, University of Sydney, Sydney, New South Wales, Australia.
  • ,
  • Rémi Fromentin, Centre de Recherche du Centre Hospitalier de l'Université de Montréal.
  • ,
  • Nicolas Chomont, Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada
  • ,
  • Rafick-Pierre Sékaly, Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
  • ,
  • Paul U Cameron, Department of Infectious Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia., The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC, AUS.
  • ,
  • Sharon R Lewin, Department of Infectious Diseases, Monash University and Alfred Health, Melbourne, Victoria, Australia., The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC, AUS.

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.

OriginalsprogEngelsk
TidsskriftAIDS
Vol/bind32
Nummer11
Sider (fra-til)1491-1497
Antal sider7
ISSN0269-9370
DOI
StatusUdgivet - 2018
Eksternt udgivetJa

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