Role of PD-1, TIGIT and TIM3 on NK cell exhaustion and function in HIV/HCV coinfection, and the impact of HCV elimination in the long term

ARIEL AMADEO OSEGUEDA PEÑA ; AILEN PERBEILS; ALEJANDRA URIOSTE; SILVIA PAZ; GABRIELA TURK; MARÍA FLORENCIA QUIROGA; YANINA GHIGLIONE; MARÍA LAURA POLO; NATALIA LAUFER

Conferencia; The 24th International AIDS Conference; 2022

Background: NK cells negatively modulate liver fibrosis (LF), therefore, playing an important role in liver pathologies. Previously, we demonstrated that NK cells from cirrhotic HCV/HIV-coinfected individuals (HCV/HIV+) displayed impaired functionality and high PD-1 expression.Here, we aimed to study PD-1, TIGIT and Tim3 as potential exhaustion markers in NK cells from HCV/HIV+ with mild and advanced LF. Also, to evaluate the role of PD-1 on NKcell function in HCV/HIV+ after HCV clearance by directacting antivirals (DAA).Methods: PBMCs were isolated from 37 HCV/HIV+ under ART (20 METAVIR F0/F1, 55% Females and 18 F4, 39% Females, evaluated by transient elastography), 6 HIVmonoinfected (HIV+, 67% Females) and 8 HCV-monoinfected (HCV+, 38% Females) individuals. In 24 individuals,samples were collected before (BSL), end (EOT) and 12 months (12MPT) after successful DAA treatment. NK-celpercentage, immunophenotype (PD-1, TIGIT and Tim3 expression) and degranulation capacity (CD107a assay) were determined by flow cytometry. Non-parametrictests were used to analyze data.Results: Mean CD4 count: 740±293, 577±339, 944±274 cells/μL for F0/F1, F4 and HIV+, respectively; all with undetectable VL. Unlike PD-1, neither TIGIT nor Tim3 were expresseddifferently in F0/F1 and F4. Degranulation of NK/PD-1+ cells was reduced in F4(p=0.039), while NK/TIGIT+ cells showed diminished CD107a expression in both groups (F0/F1: p=0.016/F4: p=0.023).Tim3 did not affect NK cell degranulation. After DAA, F4 NK cell frequency was improved betweenBSL-12MPT (p=0.039) reaching similar levels of HIV+ and HCV+, %NK/PD-1+ diminished at EOT and 12MPT (p=0.015, p=0.03), with no change in CD107a expression.In F0/F1, no changes in NK cell frequency or %NK/PD-1+ were observed, however, CD107a expression increased between BSL and 12MPT (p=0.03). Conclusions: PD-1 was the only exhaustion marker expressed differentially between F0/F1 and F4 groups. TIGIT emerged as a marker of lower NK cell functionality.Although DAA improved exhaustion and frequency of NK cells in cirrhotic individuals, functionality was only reverted in mild LF, remarking the importance of an early DAA treatment.Results suggest that addition of biological agents (eg. anti-PD-1) might boost this effect and modify LF progression.