Markers of Natural Killer Cell Exhaustion in HIV/HCV Coinfection and Their Dynamics After HCV Clearance Mediated by Direct-Acting Antivirals

Ariel Osegueda; Maria Laura Polo; Lucia Baquero; Alejandra Urioste; Yanina Ghiglione; Silvia Paz; Gabriela Poblete; Virginia Gonzalez Polo; Gabriela Turk; Maria Florencia Quiroga; Natalia Laufer

doi:10.1093/ofid/ofad591

Markers of Natural Killer Cell Exhaustion in HIV/HCV Coinfection and Their Dynamics After HCV Clearance Mediated by Direct-Acting Antivirals

Open Forum Infect Dis. 2023 Nov 22;10(12):ofad591. doi: 10.1093/ofid/ofad591. eCollection 2023 Dec.

Authors

Ariel Osegueda^{1

2}, Maria Laura Polo^{1

2}, Lucia Baquero^{1

3}, Alejandra Urioste^{1

2}, Yanina Ghiglione^{1

2}, Silvia Paz⁴, Gabriela Poblete⁴, Virginia Gonzalez Polo^{1

2}, Gabriela Turk^{1

3}, Maria Florencia Quiroga^{1

3}, Natalia Laufer^{1

3}

Affiliations

¹ CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina.
² Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina.
³ Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina.
⁴ Hospital Francisco Javier Muñiz, Buenos Aires, Argentina.

Abstract

Background: Liver fibrosis is a leading cause of morbimortality in people with HIV/hepatitis C virus (HCV). Natural killer (NK) cells are linked with amelioration of liver fibrosis; however, NK cells from individuals coinfected with HIV/HCV with cirrhosis display 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 persons coinfected with HIV/HCV with mild and advanced liver fibrosis. We also evaluated the role of PD-1 expression on NK cells after HCV clearance by direct-acting antivirals (DAAs).

Methods: Peripheral blood mononuclear cells were isolated from individuals coinfected with HIV/HCV (N = 54; METAVIR F0/F1, n = 27; F4, evaluated by transient elastography, n = 27). In 26 participants, samples were collected before, at the end of, and 12 months after successful DAA treatment. The frequency, immunophenotype (PD-1, TIGIT, and Tim3 expression), and degranulation capacity (CD107a assay) of NK cells were determined by flow cytometry.

Results: Unlike PD-1, Tim3 and TIGIT were comparably expressed between persons with mild and advanced fibrosis. Degranulation capacity was diminished in NK/TIGIT⁺ cells in both fibrosis stages, while NK/PD-1⁺ cells showed a lower CD107a expression in cirrhotic cases. Twelve months after DAA treatment, those with advanced fibrosis showed an improved NK cell frequency and reduced NK/PD-1⁺ cell frequency but no changes in CD107a expression. In individuals with mild fibrosis, neither PD-1 nor NK cell frequency was modified, although the percentage of NK/CD107a⁺ cells was improved at 12 months posttreatment.

Conclusions: Although DAA improved exhaustion and frequency of NK cells in cirrhotic cases, functionality was reverted only in mild liver fibrosis, remarking the importance of an early DAA treatment.

Keywords: HIV/HCV coinfection; NK cell exhaustion; direct-acting antivirals; immunology; liver fibrosis.