Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy.

Autor:	Uldrick TS; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.; University of Washington, Seattle, WA 98109, USA.; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Adams SV; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Fromentin R; Department of Microbiology, Infectiology, and Immunology, Université de Montréal and Centre de Recherche du CHUM, Montréal H2X0A9, Canada., Roche M; RMIT University, Melbourne, VIC 3083, Australia.; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia., Fling SP; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Gonçalves PH; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Lurain K; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Ramaswami R; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Wang CJ; University of California, San Francisco, San Francisco, CA 94110, USA., Gorelick RJ; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Welker JL; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., O'Donoghue L; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Choudhary H; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Lifson JD; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Rasmussen TA; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus 8200, Denmark., Rhodes A; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia., Tumpach C; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia., Yarchoan R; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Maldarelli F; HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA., Cheever MA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Sékaly R; Emory University, Atlanta, GA 30322, USA., Chomont N; Department of Microbiology, Infectiology, and Immunology, Université de Montréal and Centre de Recherche du CHUM, Montréal H2X0A9, Canada., Deeks SG; University of California, San Francisco, San Francisco, CA 94110, USA., Lewin SR; Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.; Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.; Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 Jan 26; Vol. 14 (629), pp. eabl3836. Date of Electronic Publication: 2022 Jan 26.
DOI:	10.1126/scitranslmed.abl3836
Abstrakt:	In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4 + T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4 + T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4 + T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.
Databáze:	MEDLINE
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