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

VA Evans, RM Van Der Sluis, A Solomon… - Aids, 2018 - journals.lww.com
VA Evans, RM Van Der Sluis, A Solomon, A Dantanarayana, C McNeil, R Garsia, S Palmer
Aids, 2018journals.lww.com
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 high and PD-1 low/− nonproliferating CD4+ …
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 high and PD-1 low/− 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 high compared with PD-1 low/-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.
Lippincott Williams & Wilkins