MARKERS OF CD4+ AND CD8+ T-CELL EXHAUSTION IN HIV/HCV COINFECTED IMMUNOLOGICAL NON-RESPONDERS TO ANTIRETROVIRAL THERAPY

Abstract

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a risk factor for immunological non-response to antiretroviral therapy. In cases of immunological non-response, HIV viral load suppression occurs without an increase in CD4+ T-cell counts, heightening the risk of morbidity and mortality in infected individuals. T-cell exhaustion may hinder their regeneration in immunological non-responders. This study aimed to identify markers of CD4+ and CD8+ T-cell exhaustion in HIV/HCV coinfected immunological non-responders. The study examined three clinical groups: 1) HIV/HCV coinfected immunological non-responders (CD4+ T-cells <350/µl blood; n=9), 2) HIV/HCV coinfected individuals with a standard response to therapy (CD4+ T-cells >500/µl blood; n=9), and 3) relatively healthy volunteers without HIV and HCV infections (n=9). Ex vivo, the number of CD4+ and CD8+ T-cells expressing the inhibitory receptor PD-1 was determined using multi-color flow cytometry. In the 7-day in vitro experiment, cell cultures were stimulated with phytohemagglutinin. The number of dying proliferated CD4+ and CD8+ T-cells (CFSElowZombieUV+) was determined using multi-color flow cytometry. The amount of interleukin-2 in the culture supernatants was measured using an enzyme-linked immunosorbent assay. It was found that in HIV/HCV coinfected immunological non-responders, there was a higher number of CD4+ and CD8+ T-cells expressing PD-1, a phenotypic marker of exhaustion, compared to the other two groups. Furthermore, the frequency of dying dividing T-cells was higher in immunological non-responders, with an increase in CD4+ T-cells but not CD8+ T-lymphocytes. Similarly, a decrease in interleukin-2 production was found in stimulated T-cells of HIV/HCV coinfected immunological non-responders in the CD4+ T-cell pool, but not in CD8+ T-lymphocytes. Thus, in HIV/HCV coinfected immunological non-responders, CD4+ T-cells appear exhausted both phenotypically and functionally. While CD8+ T-cells express inhibitory receptors, they do not show functional impairments. It appears that the specialized therapy for HIV/HCV coinfected immunological non-responders should aim to improve CD4+ T-cell function.