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 3

PD-1 blockade during suppressive ART (phase II) results in T cell proliferation and potential destabilization of the viral reservoir.

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PD-1 blockade during suppressive ART (phase II) results in T cell prolif...
(A) Ki-67 expression on CD4+ T cells, CD8+ T cells, and GagCM9+CD8+ T cells in blood after first PD-1 Ab infusion (right: saline, n = 2; single anti–PD-1 treated [ST], n = 3; double anti–PD-1 treated [DT], n = 5). Data are shown as the mean ± SEM. (B) Frequency of granzyme B+CD8+ T cells (saline, n = 5; ST, n = 3; DT, n = 10), CXCR5+GagCM9+CD8+ T cells (saline, n = 3; ST, n = 2; DT, n = 5), and CXCR5+CD4+ T cells (saline, n = 5; ST, n = 3; DT, n = 10) in axillary lymph nodes (ALN) at 2 weeks after last PD-1 Ab infusion. Viral outgrowth assay on CD4+ T cells from blood of RMs 2 weeks after the last PD-1 Ab infusion. (C) SIV Gag RNA copies/ml assayed from culture supernatant at days 9, 17, and 25 of culture. (D) Representative p27 gag staining and (E) frequency of p27 gag+ CEM cells from day 25 of viral outgrowth assay. For viral outgrowth assay, saline, n = 4; ST, n = 5; DT, n = 8. Unfilled circles indicate values from Mamu-A*01 RMs. Bars indicate the mean. Exact P values are shown. Two-way ANOVA (A), 2-tailed Mann-Whitney test (B and C), 1-way ANOVA with Dunn’s multiple-comparisons test (B, right), or 2-tailed Student’s t test (E) were used. One saline control animal was interrupted from ART early due to significant weight loss and therefore data are not available for this animal. Unless otherwise noted, saline, n = 4; ST, n = 5; DT, n = 10.