Background
HIV infection leads to significant loss of CD4 T lymphocytes (CD4TL), compromising immune function despite antiretroviral therapy (ART). People living with HIV (PLHIV) can be categorized as immune responders (IR) or immune non-responders (INR) based on their ability to achieve immune reconstitution. IR restore CD4TL counts >500 cells/mm³, while INR remain below this threshold despite ART. CD4TL subpopulations show distinct metabolic signatures based on their functions. Upon in-vitro activation, Glut1 expression rises supporting glycolysis along with the upregulation of the activation markers. Recent research has shown that CD4TL from PLHIV exhibit bioenergetic defects, particularly in INR, with a downregulation of TFAM, a regulator of mitochondrial biogenesis. In addition, the release of mitokines in the plasma is associated with mitochondrial stress. These mitochondrial dysregulations impair immune functions. We carried a study in PLHIV to describe mitochondrial defects in PLVIH to understand how IR despite those defects could achieve their immune reconstitution.
Methods
We included 30 PLHIV based on age, ART length, undetectable virus, CD4TL count and CD4/CD8 ratio. We performed a multiapproach immuno-metabolic profiling of CD4TL and their subpopulations using flow cytometry, biochemistry, and Seahorse analysis, combined with NMR metabolomics and secretome analysis on plasma
Results
CD4TL from INR displayed reduced mitochondrial mass, increased non-mitochondrial oxygen consumption, lower TFAM, increased activation markers (CD25, CD69, HLA-DR, CD95, PD-1), less naive CD4TL (p=0.007), and more TEMRA (p=0.002) compared to healthy donors (HD) and IR. However, both groups exhibited bioenergetic defects; yet IR can compensate through enhanced mitochondrial biogenesis by increasing TFAM and functional mitophagy, maintaining immune integrity. Upon in-vitro activation, INR did not upregulate Glut1 despite elevated activation markers (compared to HD: ns for IR; p<0.001 for INR). Both groups had high GDF15 in plasma, but INR showing significantly higher levels (compared to HD: p=0.022 for IR; p<0.001 for INR)
Conclusions
IR compensate for bioenergetic and immunological defects via accelerated mitochondrial biogenesis, preserving immune function. In contrast, INR show inadequate compensation, contributing to their distinct immunological profile. Strategies to enhance mitochondrial biogenesis or repair autophagy defects may improve immune function in INR, potentially converting them into IR.
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