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Metabolic targeting of HIV infection-induced myeloid-derived suppressor cells
Amir Al-Khami, Paulo Rodriguez, Christopher Parsons, Augusto Ochoa
Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans LA
Myeloid-derived suppressor cells (MDSCs) accumulate in patients with cancer and chronic
inflammatory diseases. We found that HIV-infected patients have increased numbers of
circulating granulocytic MDSCs (G-MDSCs) that upregulate the major immunosuppressive
pathways and inhibit T cell proliferation. MDSC numbers correlate with viral titers and are
inversely proportional to CD4 T cell numbers, suggesting that G-MDSCs may play a role in the
pathogenesis of the disease. We recently reported that tumor-associated MDSCs activate fatty
acid oxidation (FAO) and, at the same time, upregulate their immunosuppressive mechanisms.
Importantly, FAO inhibitors block MDSC function and induce a strong anti-tumor T cell
response. The metabolic characteristics of G-MDSCs in HIV+ patients are unknown, and the
potential role of FAO inhibition as a means of enhancing anti-retroviral therapy and
reestablishing T cell function is unclear. Therefore, we hypothesize that “G-MDSCs in HIV+
patients increase FAO that supports the activation of their immunosuppressive mechanisms;
FAO inhibition will block G-MDSC function and enhance T cell activity, thus potentiating the
effect of anti-retroviral therapies”. To test this hypothesis, we plan to (1) determine the primary
metabolic pathway used by G-MDSCs from HIV+ patients at different disease stages and
establish its role in the activation of immunosuppressive mechanisms and (2) determine the
effect of FAO inhibitors on G-MDSC function and HIV-specific T cell response.
This study is funded in part by 1P30GM114732-01 to A. Ochoa (Pilot Project #2, A. Al-Khami).