Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells.

Mohammad Haque,Xiaofang Xiong,Anil Kumar,Hao-Yun Peng,Liqing Wang,Jugal Kishore Das,Jianxun Song,Fengyang Lei,Yijie Ren

doi:10.3390/v13050753

Abstract

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

Highlights

While antiretroviral therapy (ART) in human immunodeficiency virus (HIV) infection is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue
We develop a practical system to generate HIV-1 Gag epitope SL9specific cytotoxic T lymphocytes (CTLs) from induced pluripotent stem cells, i.e., iPSC-CTLs, which present the typical T cell features, including expressions of CD3, CD8 and T cell receptor (TCR), and production of cytokines including IFN-γ
We show that a chimeric HIV-1, EcoHIV, induced HIV replication in mice; adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed HIV replication in the peritoneal macrophages and spleen in the animal model

Summary

Introduction

While antiretroviral therapy (ART) in human immunodeficiency virus (HIV) infection is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Active ART (HAART) consists of the combination of > three antiretroviral (ARV) medications to greatly suppress the HIV virus and prevent the disease progression from acute HIV infection, and chronic HIV infection to acquired immune deficiency syndrome (AIDS). Enormous reductions have been observed in rates of death and suffering when use is made of a potent ARV regimen, in the early stages of the disease. There is still no cure for HIV infection, given the promises utilizing HAART and/or stem cell transplantation [1,2].

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Conclusion