Simian Immunodeficiency Virus (SIV)-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication

Front Immunol. 2018 Mar 20;9:492. doi: 10.3389/fimmu.2018.00492. eCollection 2018.

Abstract

There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh) located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV)-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh) cells using antiviral chimeric antigen receptor (CAR) T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured in vitro, and CXCR5-mediated migration was evaluated using both an in vitro transwell migration assay, as well as a novel ex vivo tissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVmac239 and SIVE660 replication in in vitro and migration to the ligand CXCL13 in vitro, and concentration in B cell follicles in tissues ex vivo. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure) of HIV and SIV infections.

Keywords: B cell follicles; CAR-T cells; CD8+ T cells; CXCR5; HIV; HIV cure strategies; chimeric antigen receptor; simian immunodeficiency virus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Chemokine CXCL13 / genetics
  • Chemokine CXCL13 / immunology
  • Gammaretrovirus
  • HIV-1 / genetics
  • HIV-1 / immunology
  • Macaca mulatta
  • Receptors, CXCR5 / genetics
  • Receptors, CXCR5 / immunology
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Simian Acquired Immunodeficiency Syndrome / genetics
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / pathology
  • Simian Acquired Immunodeficiency Syndrome / therapy*
  • Simian Immunodeficiency Virus / physiology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Transduction, Genetic*
  • Virus Replication / genetics
  • Virus Replication / immunology*

Substances

  • Chemokine CXCL13
  • Receptors, CXCR5
  • Receptors, Chimeric Antigen