Compromised Glycolysis in Memory CD4+ T Cells Derived from HIV-infected Immunological Non-responders to Highly Active Antiretroviral Therapy.

Abstract

Introduction/objective: "Immunological non-responders" (INRs) are individuals living with HIV who are undergoing Highly Active Antiretroviral Therapy (HAART) but fail to restore their CD4⁺ T-cells count despite effective viral control. The incomplete immune restoration in INRs is often associated with the low-productive proliferation of memory CD4⁺ T lymphocytes. The ability of CD4⁺ T cells to divide is critically dependent on the glycolytic pathway, which supplies the necessary energy and building blocks for cell division. We hypothesize that impaired glycolytic activity in the memory CD4⁺ T cells of INRs contributes to their ineffective proliferation, ultimately limiting immune restoration.

Methods: This study involved two groups of HIV-infected HAART-treated subjects: INR and Immunological Responders (IR). A third group consisted of healthy controls, comprising uninfected volunteers. To identify the metabolic factors contributing to immunological non-response to therapy, glucose uptake, and lactate production were measured in the memory CD4⁺ T cells from all three groups.

Results: INR had the highest activation level in memory CD4+ T cells and the greatest glucose uptake. However, both groups of HIV-infected patients had significantly reduced lactate production compared to the healthy donors. Short-term phytohemagglutinin stimulation provoked an increase in lactate production in memory CD4+ T lymphocytes. Nevertheless, we found significantly reduced lactate production levels in activated memory CD4+ Т cells of INR an IR.

Conclusion: In INRs, there is a discrepancy between the highly activated phenotype of memory CD4⁺ T lymphocytes and their glycolytic activity. This reduced glycolysis may explain the lowproductive proliferation of memory CD4⁺ T lymphocytes in INRs.