Background
CC genotype of the rs12979860 polymorphism on the lambda 4 interferon (IFNL4) gene has been related to spontaneous resolution of Hepatitis C virus (HCV) infection. The role of CC genotype in those who develop chronic HCV infection is still unknown, particularly notable during Human Immunodeficiency Virus (HIV) coinfection. To study its role in HCV/HIV coinfection, immunological characterization of rs12979860 genotypes (CC vs CT/TT) has been conducted.
Methods
Observational study in 118 people with HIV (PWH): 45 with HCV-chronic infection (CHC); 38 who spontaneously clarified HCV (SC); and 35 controls (HIV). rs12979860 was genotyped by real time PCR, expression of surface markers was evaluated in CD4+ and CD8+ memory T cells by flow cytometry, oxidative stress markers were quantified by ELISA, and 45 immune plasma markers by Luminex. Differences among genotypes were evaluated by generalized linear model (GLM), or generalized additive model for location, scale, and shape (GAMLSS), adjusted for the most significant variables and corrected by FDR.
Results
CC-carriers presented a higher frequency of SC (47.54%), as expected. Significant differences among rs12979860 genotypes in the cellular immune profile were mainly observed within CHC group. In this group, CC-carriers showed higher levels of cellular immune exhaustion in CD8+T cells, specifically middle activation (CD25) in total effector memory (EM), EM1 and EM4 subpopulations; late activation (CD38) in EM and TEMRA; and senescence (PD1/CD57) in EM, EM2, EM3 and TEMRA (pE2). Opposite, their resting CD8+T cells significantly decreased, including EM and TEMRA (total and pE2) (Fig.1a). Within SC group, CC-carriers showed significantly reduced senescence levels only in CD8+ TEMRA subpopulations. As for plasmatic markers, all CC-carriers showed a general increase in cytokines IL-2, IL-4, IL-10, IL-13 and IL-15. Also, among CHC, CC-carriers had higher levels of IL-1beta, IL-6, IL-17A, IL-27, IL-31, TNF-α, IL-1RA and GM-CSF, while oxidative stress slightly decreased (Fig.1b). No significant differences were found in HIV group.
Conclusions
The favourable rs12979860-CC genotype is associated with increased levels of exhausted CD8+T cells among the PWH with chronic HCV infection, that may be masked during clinical monitoring by the general altered levels of soluble immune markers. CD8+T cell exhaustion relates to tumorigenesis, indicating that CC carriage is unfavourable along HCV/HIV coinfection and should be considered during clinical management.
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