Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease

Nat Immunol. 2019 Aug;20(8):1059-1070. doi: 10.1038/s41590-019-0418-x. Epub 2019 Jul 15.

Abstract

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.

Publication types

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

MeSH terms

  • Anti-HIV Agents / therapeutic use*
  • Gene Expression / drug effects*
  • Gene Expression Profiling
  • HIV Infections / drug therapy*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • Humans
  • Receptors, CXCR5 / metabolism
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / pathology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology
  • Th17 Cells / pathology*
  • Viral Load / drug effects
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • CXCR5 protein, human
  • Receptors, CXCR5