HCV coinfection contributes to HIV pathogenesis by increasing immune exhaustion in CD8 T-cells

Abstract

Background: There are several contributors to HIV-pathogenesis or insufficient control of the infection. However, whether HIV/HCV-coinfected population exhibits worst evolution of HIV-pathogenesis remains unclear. Recently, some markers of immune exhaustion have been proposed as preferentially upregulated on T-cells during HIV-infection. Herein, we have analyzed T-cell exhaustion together with several other contributors to HIV-pathogenesis that could be affected by HCV-coinfection.

Patients and methods: Ninety-six patients with chronic HIV-infection (60 HIV-monoinfected and 36 HIV/HCV-coinfected), and 20 healthy controls were included in the study. All patients were untreated for both infections. Several CD4 and CD8 T-cell subsets involved in HIV-pathogenesis were investigated. Non-parametric tests were used to establish differences between groups and associations between variables. Multivariate linear regression was used to ascertain the variables independently associated with CD4 counts.

Results: HIV-patients presented significant differences compared to healthy controls in most of the parameters analyzed. Both HIV and HIV/HCV groups were comparable in terms of age, CD4 counts and HIV-viremia. Compared to HIV group, HIV/HCV group presented significantly higher levels of exhaustion (Tim3+PD1- subset) in total CD8+ T-cells (p = 0.003), and higher levels of exhaustion in CD8+HLADR+CD38+ (p = 0.04), CD8+HLADR-CD38+ (p = 0.009) and CD8+HLADR-CD38- (p = 0.006) subsets of CD8+ T-cells. Interestingly these differences were maintained after adjusting by CD4 counts and HIV-viremia.

Conclusions: We show a significant impact of HCV-coinfection on CD8 T-cells exhaustion, an important parameter associated with CD8 T-cell dysfunction in the setting of chronic HIV-infection. The relevance of this phenomenon on immunological and/or clinical HIV progression prompts HCV treatment to improve management of coinfected patients.

Fig 1. Levels of CD4 T-cell subsets.

Box-plot graphs showing the levels of CD4 T-cell subsets in healthy controls (clear boxes), HIV (light grey boxes) and HIV/HCV (dark grey boxes) patients. Upper graph shows levels of different CD4 subsets on the basis of CD45RA, CD31 and Ki67 expression. Right vertical axis applies only for subsets defined by Ki67 and CD31. Middle graph shows levels of apoptosis (CD95) and senescence (CD57) on different subsets of CD4 cells; and lower graph the levels of exhaustion (PD1 and Tim3 markers) on different subsets of CD4 cells. Statistically significant differences between healthy controls and all patients are marked by an asterisk; and differences between the two groups of patients by ¶ symbol.

Fig 2. Levels of exhaustion markers on CD8 T-cells.

Box-plot graph showing the level of exhaustion (PD1 and Tim3 markers) on different subsets of CD8 T-cells in healthy controls (clear boxes), HIV (light grey boxes) and HIV/HCV (dark grey boxes) patients. Statistically significant differences between healthy controls and all patients are marked by an asterisk; and differences between the two groups of patients by symbol.