(913) Persistent NK Cell Dysfunction May Be Linked to Gut Dysbiosis in HIV Despite Long-Term Antiretroviral Therapy (ART)

Introduction/Rationale: Natural killer (NK) cells are critical for controlling HIV and other infectious and non-infectious diseases. Although antiretroviral therapy (ART) suppresses HIV viral loads and restores CD4+T cells, NK cell dysfunction persists, potentially compromising long-term health in people living with HIV(PLWH).

Methods: We compared immune signatures in peripheral blood mononuclear cells and gut integrity biomarkers between age-matched individuals without HIV (PWoH) (n=15) and adult PLWH (n=13) during viremia and ART-mediated viral suppression ( < 50c/mL; ~5 years post-ART) using high dimensional flow cytometry and plasma biomarker profiling. Pearson correlation and one-way ANOVA were used for analyses.

Results: Compared to PWoH, PLWH exhibited a reduction in CD56briCD16- and CD56dimCD16- NK cells during viremia (pre-ART), with these levels remaining low post-ART. In contrast, CD56dimCD16+ NK cells expanded during pre-ART and remained elevated post-ART. There were sustained increases in activation markers (CD69, NKp44, HLA-DR) and memory markers (NKG2C, CD57) in these NK subsets both before and after ART. Despite ART, dysregulation of chemokine receptors (CCR2, CCR5, CCR7, CXCR5) in these NK subsets did not return to the levels seen in PWoH. Many NK subsets in PLWH showed reduced pro-inflammatory (IFNγ, IL-1β) and anti-inflammatory (TGFβ, IL-10) cytokine responses, as well as reduced polyfunctionality to both HIV-specific and non-specific stimuli, with no recovery despite ART. Plasma levels of intestinal fatty acid binding protein (IFAB), a marker of microbial translocation, were elevated in PLWH during viremia, and were positively correlated with memory-like (CD57+, NKG2C+) and activated (CD69+) in NK cell subsets in PLWH. (p < 0.05 for all).

Conclusion: These findings suggest that persistent NK cell dysregulation may be linked to gut dysbiosis in PLWH, underscoring the need for improved therapeutic strategies that focus on immune restoration through gut health.