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

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• Human Immunodeficiency Virus (HIV) infection leads to CD4 T cell depletion, a hallmark of Acquired Immunodeficiency Syndrome (AIDS).
• Antiretroviral therapy (ART) effectively controls HIV, but some individuals, known as immune non-responders (INRs), fail to achieve complete immune reconstitution.
• The mechanisms behind incomplete CD4 T cell recovery in people living with HIV (PLHIV) are not fully understood.

Purpose of the Study:

• To investigate the mechanisms underlying incomplete CD4 T cell recovery in PLHIV, focusing on mitochondrial function.
• To characterize the phenotype and function of CD4 T cells in PLHIV, particularly in INRs.
• To explore the role of mitochondrial transcription factor A (mtTFA) in CD4 T cell homeostasis in HIV infection.

Main Methods:

• Phenotypic and functional characterization of CD4 T cells from PLHIV.
• Analysis of mitochondrial functions in CD4 T cells.
• Transcriptional profiling and flow cytometry to assess mtTFA levels and T cell activation states.

Main Results:

• CD4 T cells in PLHIV, especially INRs, show diminished numbers but expanded cycling populations.
• HIV-INR CD4 T cells exhibit heightened activation, exhaustion, and senescence phenotypes with impaired mitochondrial function.
• A significant repression of mitochondrial transcription factor A (mtTFA) was observed in CD4 T cells from PLHIV, disrupting T cell homeostasis.

Conclusions:

• HIV infection triggers a cascade of T cell dysfunction, including over-activation, exhaustion, senescence, and apoptosis, linked to compromised mitochondrial function.
• Repression of mtTFA plays a critical role in the abnormal mitochondrial and T cell homeostasis observed in PLHIV.
• Targeting the mtTFA pathway could be a potential adjunctive immunotherapy to restore CD4 T cell function in ART-treated PLHIV, particularly INRs.