Persistent expansion and Th1-like skewing of HIV-specific circulating T follicular helper cells during antiretroviral therapy

EBioMedicine. 2020 Apr;54:102727. doi: 10.1016/j.ebiom.2020.102727. Epub 2020 Apr 5.


Background: Untreated HIV infection leads to alterations in HIV-specific CD4+ T cells including increased expression of co-inhibitory receptors (IRs) and skewing toward a T follicular helper cell (Tfh) signature. However, which changes are maintained after suppression of viral replication with antiretroviral therapy (ART) is poorly known.

Methods: We analyzed blood CD4+ T cells specific to HIV and comparative viral antigens in ART-treated people using a cytokine-independent activation-induced marker assay alone or in combination with functional readouts.

Findings: In intra-individual comparisons, HIV-specific CD4+ T cells were characterized by a larger fraction of circulating Tfh (cTfh) cells than CMV- and HBV-specific cells and preferentially expressed multiple IRs and showed elevated production of the Tfh cytokines CXCL13 and IL-21. In addition, HIV-specific cTfh exhibited a predominant Th1-like phenotype and function when compared to cTfh of other specificities, contrasting with a reduction in Th1-functions in HIV-specific non-cTfh. Using longitudinal samples, we demonstrate that this distinct HIV-specific cTfh profile was induced during chronic untreated HIV infection, persisted on ART and correlated with the translation-competent HIV reservoir but not with the total HIV DNA reservoir.

Interpretation: Expansion and altered features of HIV-specific cTfh cells are maintained during ART and may be driven by persistent HIV antigen expression.

Funding: This work was supported by the National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR) and the FRQS AIDS and Infectious Diseases Network.

Keywords: Antiretroviral therapy (ART); HIV; HIV-specific CD4(+) T cells; T Follicular helper T cells.

MeSH terms

  • Anti-HIV Agents / therapeutic use*
  • Cells, Cultured
  • Chemokine CXCL13 / metabolism
  • HIV Infections / blood*
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • Humans
  • Interleukins / metabolism
  • T Follicular Helper Cells / immunology*
  • Th1 Cells / immunology*


  • Anti-HIV Agents
  • CXCL13 protein, human
  • Chemokine CXCL13
  • Interleukins
  • interleukin-21