PD-1 expression is linked to NK cell dysfunction and advanced liver fibrosis in HIV/HCV-coinfected individuals

MARÍA LAURA POLO; ALEJANDRA URIOSTE; VIRGINIA GONZALEZ POLO; GABRIELA POBLETE; ANA MARTINEZ; ALICIA SISTO; MARÍA JOSÉ ROLÓN; GABRIELA TURK; NATALIA LAUFER

San Francisco

Conferencia; 23RD INTERNATIONAL AIDS CONFERENCE (VIRTUAL); 2020

Background: liver disease is one of the leading causes of morbi-mortality in people living with HIV/HCV. Response to HCV therapy and fibrosis regression after HCV clearance is diminished in cirrhotic patients, together with increased risk of hepatocellular carcinoma. Natural killer cells (NK) are associated with tumoral and viral control, and also amelioration of liver fibrosis; however, frequency and degranulation of NK cells is reduced in cirrhotic HIV/HCV-coinfected individuals. Here, we aim to further study NK cell activation and exhaustion in progressive stages of hepatic fibrosis secondary to HIV/HCV coinfection.Methods: Blood samples from ART-treated HCV/HIV-coinfected participants with different liver fibrosis levels (mild: METAVIR F0/F1 n=16; advanced: F4 n=18, assessed by transient elastography) were collected and PBMCs purified. Immunophenotyping (CD25, CD69, NKp46, NKG2D, and PD-1 expression) and degranulation capacity (CD107a assay) of NK cells were studied by flow cytometry. Clinical and experimental data were analyzed using non-parametric statistics.Results: All participants had undetectable HIV viral load (VL) with a median LT-CD4 of 646 cel/μl (IQR 394-849). Overall, 47% were female, median age: 49 years (IQR 46.75-53), time of known HIV infection: 20 years (IQR 17.5-23), HCV infection: 14 years (IQR 10.5-20), time on ART: 11.5 years (IQR 7.75-18.35). HCV genotype was predominantly 1a, HCV VL: 6.96 log10 copies (IQR 5.91-16). None of the above parameters differed between groups. NK cell expression of PD-1 (p=0.002) and frequency of NK/PD-1+ cells (p=0.006) were upregulated in F4 participants. In both groups, PD-1 was confined to CD56dim subset (F0/F1: p=0.002; F4: p=0.015) and was associated with higher CD69 and CD25 expression. In NK cells, PD-1 expression inversely correlated with NK cell frequency (r=-0.50; p=0.01) and degranulation capacity (r=-0.63; p=0.002). Additionally, PD-1 expression positively correlated with APRI score (r=0.53; p=0.02), liver stiffness (r=0.51; p=0.01), and AST levels (r=0.52; p=0.02), and negatively with albumin (r=-0.6; p=0.01) and prothrombin time (r=-0.57; p=0.01).Discussion: Cirrhosis is associated to NK cell exhaustion in HIV/HCV-coinfected individuals. Potential interventions to improve NK cell dysfunction may have relevant implications for improve HCV treatment success in cirrhotic individuals, as well as potential NK cell-based immunotherapies targeted to modulate liver fibrosis or counteract malignant transformation.