CTLA-4+PD-1- Memory CD4+ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

Immunity. 2017 Oct 17;47(4):776-788.e5. doi: 10.1016/j.immuni.2017.09.018.

Abstract

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1- memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh cells, SIV-enriched CTLA-4+PD-1- CD4+ T cells were found outside the B cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1- memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.

Keywords: CTLA-4; HIV; PD-1; SIV; T follicular helper cells; animal models; co-inhibitory receptors; latent viral reservoir; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Retroviral Agents / therapeutic use*
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • CTLA-4 Antigen / immunology*
  • CTLA-4 Antigen / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / immunology
  • HIV-1 / physiology
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunologic Memory / drug effects
  • Immunologic Memory / immunology
  • In Situ Hybridization
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Lymph Nodes / virology
  • Macaca mulatta
  • Microscopy, Confocal
  • Programmed Cell Death 1 Receptor / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • Simian Acquired Immunodeficiency Syndrome / drug therapy*
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / drug effects*
  • Simian Immunodeficiency Virus / immunology
  • Simian Immunodeficiency Virus / physiology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / virology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / virology

Substances

  • Anti-Retroviral Agents
  • CTLA-4 Antigen
  • Programmed Cell Death 1 Receptor