Combination anti–PD-1 and antiretroviral therapy provides therapeutic benefit against SIV
Geetha H. Mylvaganam, … , Rafi Ahmed, Rama R. Amara
Geetha H. Mylvaganam, … , Rafi Ahmed, Rama R. Amara
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e122940. https://doi.org/10.1172/jci.insight.122940.
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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 1

PD-1 blockade administered prior to ART (phase I) results in improved T cell functionality in SIV-infected RMs.

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PD-1 blockade administered prior to ART (phase I) results in improved T ...
(A) Schematic of PD-1 blockade strategy during phase I and II. (B) Frequency of Ki-67+CD4+ and Ki-67+CD8+ T cells in the blood. (C) Frequency of SIV Gag-specific and Env-specific IFN-γ– and TNF-α–producing CD4+ and CD8+ T cells in the blood. (D) Percentage of Ki-67+, granzyme B+, and CXCR5+GagCM9+ CD8+ T cells in the blood (saline, n = 6; PD-1 Ab treated, n = 5). (E) Gene set enrichment analysis (GSEA) of RNA-Seq data from blood at day 10 compared with day 0 following PD-1 blockade during phase I (PD-1 Ab treated, n = 10). Normalized enrichment scores for select upregulated and downregulated gene sets depicted. Dashed line indicates normalized enrichment score cutoff of greater than 1.35 for upregulated gene sets and less than –1.35 for downregulated gene sets with a false discovery rate of less than 0.2. (F) GSEA plots comparing day 10 (D10) to day 0 (D0) of phase I for PD-1 Ab– and saline-treated (n = 5) groups. Leading-edge genes from gene sets are shown as black outlined dots. Shaded gray area depicts ART. Unfilled circles indicate values from Mamu-A*01 RMs. Data in B and C are shown as the mean ± SEM. **P < 0.01; ***P < 0.001 by 2-way ANOVA (B and C) or 2-tailed paired Student’s t test (D). n = 10 per group unless otherwise noted.