CTL-mediated immunotherapy can suppress SHIV rebound in ART-free macaques

Jin Fan,Hua Liang,Cassian Yee,Hong Peng,Jing Xue,Xiaolin Ji,Yiming Shao,Chuan Qin,Shuo Wang,Dan Li

doi:10.1038/s41467-019-09725-6

Abstract

A major barrier to human immunodeficiency virus (HIV) cure is the existence of viral reservoirs that lead to viral rebound following discontinuation of antiretroviral therapy (ART). We postulate that enhancing cytotoxic T lymphocytes (CTL) targeting conserved envelope (Env) regions can eliminate HIV infected cells in latency. Here, we evaluate the use of adoptively transferred HIV vaccine-induced subtype C Env-specific CTLs in a macaque subtype B simian-human immunodeficiency virus (SHIV) model to determine whether plasma viremia can be controlled after ART interruption. We demonstrate that adoptive cellular therapy (ACT) using autologous Env-specific T cells augmented by therapeutic vaccination can suppress ART-free viral rebound in the SHIV model. Furthermore, phenotypic and functional characterization of adoptively transferred cells in ACT-responsive and nonresponsive animals support a critical role for cross-reactive central memory T cells in viremia control. Our study offers an approach to potentiate immunological suppression of HIV in the absence of antiviral drugs.

Highlights

A major barrier to human immunodeficiency virus (HIV) cure is the existence of viral reservoirs that lead to viral rebound following discontinuation of antiretroviral therapy (ART)
We test in rhesus macaques a strategy for HIV functional cure: HIV vaccine immunization combined with antiviral treatment and suppress viral rebound with cytotoxic T lymphocytes (CTL) immunotherapy after ART interruption
We propose a therapeutic approach to achieving HIV functional cure by eliciting HIV-specific CTL in vivo using an HIV vaccine to stimulate HIV-specific CTL during ART and, subsequently, amplifying this response ex vivo for adoptive cell therapy as a means of providing long-term suppression of viral rebound following ART interruption

Summary

Introduction

A major barrier to human immunodeficiency virus (HIV) cure is the existence of viral reservoirs that lead to viral rebound following discontinuation of antiretroviral therapy (ART). We evaluate the use of adoptively transferred HIV vaccine-induced subtype C Env-specific CTLs in a macaque subtype B simian-human immunodeficiency virus (SHIV) model to determine whether plasma viremia can be controlled after ART interruption. We demonstrate that adoptive cellular therapy (ACT) using autologous Env-specific T cells augmented by therapeutic vaccination can suppress ART-free viral rebound in the SHIV model. We test in rhesus macaques a strategy for HIV functional cure: HIV vaccine immunization combined with antiviral treatment and suppress viral rebound with CTL immunotherapy after ART interruption. We show that adoptive transfer of augmented Env-specific T cells with a central memory phenotype leads to virological suppression following drug discontinuation and viral rebound. In the setting of viral rebound in an ART interruption model, that therapeutic vaccination in combination with CTL immunotherapy can be a promising approach for virologic suppression

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Conclusion