Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

Front Immunol. 2021 May 4:12:658420. doi: 10.3389/fimmu.2021.658420. eCollection 2021.


The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

Keywords: HIV; T cell exhaustion; immune non-responder; mitochondrial dysfunction; senescence.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antiretroviral Therapy, Highly Active
  • Apoptosis
  • Biomarkers
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • HIV Infections / metabolism*
  • HIV Infections / virology*
  • HIV-1* / immunology
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Stress, Physiological
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Viral Load
  • Young Adult


  • Biomarkers
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Transcription Factors
  • mitochondrial transcription factor A