Combination anti–PD-1 and antiretroviral therapy provides therapeutic benefit against SIV
Geetha H. Mylvaganam, Lynette S. Chea, Gregory K. Tharp, Sakeenah Hicks, Vijayakumar Velu, Smita S. Iyer, Claire Deleage, Jacob D. Estes, Steven E. Bosinger, Gordon J. Freeman, Rafi Ahmed, Rama R. Amara
Geetha H. Mylvaganam, Lynette S. Chea, Gregory K. Tharp, Sakeenah Hicks, Vijayakumar Velu, Smita S. Iyer, Claire Deleage, Jacob D. Estes, Steven E. Bosinger, Gordon J. Freeman, Rafi Ahmed, Rama R. Amara
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Research Article AIDS/HIV Immunology

Combination anti–PD-1 and antiretroviral therapy provides therapeutic benefit against SIV

Abstract

Therapeutic strategies that augment antiviral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The coinhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of antiviral CD8+ T cells and B cells. Here, we tested the immunological and virological effects of PD-1 blockade combined with antiretroviral therapy (ART) in rhesus macaques. Administration of anti–PD-1 antibody 10 days prior to ART initiation rapidly enhanced antiviral CD8+ T cell function and diminished IFN-stimulated genes. This resulted in faster viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. PD-1 blockade during ART resulted in lower levels of cell-associated replication-competent virus. Following ART interruption, PD-1 antibody–treated animals showed markedly higher expansion of proliferating CXCR5+perforin+granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in better control of viremia. Our results show that PD-1 blockade can be administered safely with ART to augment antiviral CD8+ T cell function and reduce the viral reservoir, leading to improved control of viral rebound after ART interruption.

Authors

Geetha H. Mylvaganam, Lynette S. Chea, Gregory K. Tharp, Sakeenah Hicks, Vijayakumar Velu, Smita S. Iyer, Claire Deleage, Jacob D. Estes, Steven E. Bosinger, Gordon J. Freeman, Rafi Ahmed, Rama R. Amara

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Figure 2

PD-1 blockade administered prior to ART results in improved viral suppression following ART initiation.

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PD-1 blockade administered prior to ART results in improved viral suppre...
Plasma SIV RNA viral loads (copies/ml) shown as (A) geometric mean for each group and (B) for individual RMs at initiation of anti–PD-1 Ab or saline infusion. Limit of detection is 60 copies/ml. (C) Kaplan-Meier curve of number of days until viral suppression (<100 copies/ml for at least 2 or more consecutive time points). (D) Plasma SIV RNA viral loads (copies/ml) from chronically SIV-infected RMs administered humanized anti–PD-1 Ab or no Ab during ART initiation in a second study (n = 4 per group). (E) Frequency of Tcm (CD28+CD95+) CD4+ T cells in the rectum. (F) Frequency of IL-17A–producing CD4+ T cells in the rectum after PMA and ionomycin stimulation (saline, n = 9). (G) Frequency of neutrophils in lamina propria (LP) sections after 36 weeks of ART (saline, n = 5; PD-1 Ab treated, n = 6). Bars indicate the mean. Data were not collected for all animals. Shaded gray area depicts ART. Unfilled symbols indicate values from Mamu-A*01 RMs. Specific T cell frequency data are shown as mean ± SEM. *P < 0.05 by Mantel-Cox test (C), 2-way ANOVA (E and F), or 2-tailed Mann-Whitney test (G). n = 10 per group unless otherwise noted.