ABSTRACT
Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after anti-retrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIV-specific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100- to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research.
Subject(s)
Anti-Retroviral Agents , Immune Checkpoint Inhibitors , Programmed Cell Death 1 Receptor , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Anti-Retroviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Memory , Macaca mulatta , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/drug effects , Viral Load/drug effects , Viremia/drug therapyABSTRACT
Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions that may complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.
Subject(s)
HIV Infections/immunology , Programmed Cell Death 1 Receptor/metabolism , AIDS-Related Opportunistic Infections/therapy , Animals , Apoptosis , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , HIV Infections/metabolism , HIV Infections/therapy , HIV Infections/virology , Humans , Immunotherapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Signal Transduction , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Acquired Immunodeficiency Syndrome/therapy , Simian Acquired Immunodeficiency Syndrome/virologyABSTRACT
In SIV/HIV infection, the gastrointestinal tissue dominates as an important site because of the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells (DCs) in mediating immune activation and disease progression. We demonstrate that plasmacytoid DCs (pDCs) in the blood up-regulate ß7-integrin and are rapidly recruited to the colorectum after a pathogenic SIV infection in rhesus macaques. These pDCs were capable of producing proinflammatory cytokines and primed a T cytotoxic 1 response in vitro. Consistent with the up-regulation of ß7-integrin on pDCs, in vivo blockade of α4ß7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The up-regulation of ß7-integrin expression on pDCs in the blood also was observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDCs influence immune activation in colorectal tissue after pathogenic immunodeficiency virus infections.
