Abstract
Blockade of the programmed cell death protein/ligand 1 (PD-1/PD-L1) pathway with monoclonal antibodies (mAb) is now commonly used for cancer immunotherapy and has therapeutic potential in chronic viral infections including HIV-1. PD-1/PD-L1 blockade could augment HIV-1-specific immune responses and reverse HIV-1 latency, but the latter effect has not been clearly shown. We tested the ability of the human anti-PD-L1 mAb BMS-936559 and the human anti-PD-1 mAb nivolumab to increase HIV-1 virion production ex vivo from different peripheral blood mononuclear cell populations obtained from donors on suppressive antiretroviral therapy (ART). Fresh peripheral blood mononuclear cells (PBMC), CD8-depleted PBMC, total CD4+ T cells, and resting CD4+ T cells were purified from whole blood of HIV-1-infected donors and cultured in varying concentrations of BMS-936559 (20, 5, or 1.25μg/mL) or nivolumab (5 or 1.25μg/mL), with or without anti-CD3/CD28 stimulatory antibodies. Culture supernatants were assayed for virion HIV-1 RNA by qRT-PCR. Ex vivo exposure to BMS-936559 or nivolumab, with or without anti-CD3/CD28 stimulation, did not consistently increase HIV-1 virion production from blood mononuclear cell populations. Modest (2-fold) increases in virus production were observed in a subset of donors and in some cell types but were not reproducible in longitudinal samples. Cell surface expression of PD-1 and PD-L1 were not associated with changes in virus production. Ex vivo blockade of the PD-1 axis alone has limited effects on HIV-1 latency.
Highlights
Antiretroviral therapy (ART) does not cure HIV-1 infection because of a persistent reservoir of cells carrying intact proviruses that are capable of infectious virus production, leading to virus replication, spread and rebound viremia if ART is stopped [1,2,3,4,5,6,7,8]
Despite the lack of a statistically significant overall virologic response to Bristol-Myers Squibb (BMS)-936559, we investigated whether cell types or certain BMS-936559 concentrations were associated with increased virus production, defined as 2-fold greater HIV-1 RNA in supernatants from cells treated with BMS-936559 compared to isotype control
If responses were defined using a more stringent criteria of 3-fold increase in supernatant HIV-1 RNA compared to isotype control and >90 cp/mL, virus activation was observed in peripheral blood mononuclear cells (PBMC) from 4 of 11 donors, in total CD4+ T cells from 2 of 10 donors, and in resting CD4+ T cells from 0 of 8 donors
Summary
Antiretroviral therapy (ART) does not cure HIV-1 infection because of a persistent reservoir of cells carrying intact proviruses that are capable of infectious virus production, leading to virus replication, spread and rebound viremia if ART is stopped [1,2,3,4,5,6,7,8]. In chronic HIV-1 infection, immune checkpoint expression is increased both in individuals with uncontrolled viremia and in those on ART with suppression of viremia [12,13], and is associated with more rapid HIV-1 disease progression [14] and shorter time to viral rebound following ART cessation [15]. PD-L1 blockade with BMS-936559 was shown to be generally well-tolerated in HIV-1-infected participants and resulted in increased HIV-1 gag-specific polyfunctional CD8+ T cell responses [16] These preliminary data suggest that blockade of the PD-1 axis has a potential role in immune control of HIV-1. To address the possibility that immune checkpoint blockade can reverse HIV-1 latency, the effects of anti-PD-L1 (BMS-936559) or anti-PD-1 (nivolumab) mAb on virus production were assessed ex vivo with different cell populations from HIV-1-infected individuals on long-term suppressive ART. Cell viability and PD-1/PD-L1 expression were measured and examined for associations with HIV1 production
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