Friday, April 19, 2024
4/19/2024
Elevated frequencies of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) precede and contribute to immune dysfunction in persons living with HIV (PLHIV). The underlying mechanisms of this dysregulation are poorly understood. Potential mechanisms under investigation include PMN-MDSCs impacting CD4+ T cell recovery, expanding T-regulatory cells (T-reg), inducing immune checkpoints (IC), and suppressing the antiviral functions of cytotoxic lymphocytes. While the initiation of combined antiretroviral therapy (cART) can reduce peripheral blood PMN-MDSCs levels in PLHIV, PMN-MDSCs levels can remain elevated despite cART, and cART does not remedy all PMN-MDSC-induced immune dysfunction. The tumor-necrosis-factor-related- apoptosis-inducing-ligand (TRAIL) is a cell-surface and secreted apoptosis-inducing protein expressed by activated human Natural Killer (NK) cells and cytotoxic T lymphocytes (CD8+ T cells, CTL). TRAIL ligation of its receptors (also called death receptors (DRs)) induces apoptosis on DR-expressing cells. PMN-MDSCs express TRAIL-R1 (DR4) and 2 (DR5). Recently published work showed a link between serum levels of agonistic soluble TRAIL (sTRAIL) and PMN-MDSC frequency in PLHIV. Early in HIV infection, PMN-MDSC frequency inversely correlates with plasma levels of sTRAIL, and recombinant TRAIL induces PMN-MDSC apoptosis in vitro. Thus, DR ligation, currently being explored as an immunotherapy for cancer, may be a way to reduce PMN-MDSCs frequencies in PLHIV. In addition to TRAIL, PMN-MDSCs also express NKG2D-ligands. NKG2D is an NK cell activating receptor and a positive costimulatory receptor of human CTLs, and NKG2D-ligand expression renders PMN-MDSCs highly susceptible to NK cell killing. However, despite data implicating PMN-MDSCs as essential contributors to immune dysfunction and HIV disease, approaches targeting PMN-MDSCs in PLHIV have yet to be explored. Using a mouse model with a competent and HIV susceptible humanized immune system, we found that PMN-MDSCs expand rapidly upon HIV infection. Like in humans, PMN-MDSCs correlated positively with HIV viral titers and T-reg in this model. Mechanistic studies in cytotoxic lymphocyte-depleted animals revealed that NK cells and perhaps also CTLs controlled PMN-MDSC expansion, expressed NKG2D, and upregulated TRAIL upon HIV infection. We propose to explore the mechanisms by which PMN-MDSC and consequent Treg expansions are controlled. We propose to test the hypothesis that therapeutic PMN-MDSCs reduction during HIV infection prevents PMN-MDSCs-caused immune dysfunction, improving viral control. Our studies will leverage novel tools and therapeutic approaches to define the impact of the TRAIL and NKG2D pathways on controlling PMN-MDSC and resultant Treg expansion upon HIV infection. We will explore therapeutic strategies to reduce PMN-MDSC and prevent T-reg expansion upon HIV infection in vivo. The knowledge gained from our work will facilitate new insight into the mechanisms that control or exacerbate HIV-infection-induced immune disturbance and disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
