Dynamics of cellular senescence markers after HCV elimination in people living with HIV

Abstract Background: Previously, we identified that different HCV infection, either acute or chronic infection in people living with HIV (PLWHIV) drives dissimilar cellular senescence profile. However, variations in these profiles after HCV clearance, spontaneously or with direct-acting antivirals (DAAs), remains unclear. Methods: Longitudinal observational study (48 weeks of follow-up) in 70 PLWHIV with different HCV status: 23 PLWHIV with active HCV-chronic infection (CHC) before and after HCV eradication with DAAs, 12 PLWHIV who spontaneously clarify the HCV (SC), and 35 PLWHIV controls (HIV), all of them aviremic. Plasma oxidative stress biomarkers were quantified at DNA, lipid, protein, and nitrate levels, as well as the total antioxidant capacity and glutathione reductase enzyme. The replicative senescence was evaluated by relative telomere length (RTL) measurement by Monochromatic Multiplex Real-Time Quantitative PCR (MMqPCR). Finally, twenty-six factors associated to Senescence-Associated Secretory Phenotype (SASP) were characterized by Multiplex Immunoassay (Luminex xMAP technology). Differences in senescence markers was evaluated by generalized linear mixed model (GLMMs) for longitudinal series or generalized linear model (GLMs) for non-paired comparisons. Results: During follow-up, the SC group achieved a reduction of oxidative stress levels at glutathione enzyme and lipid peroxidation level. The secretion of SASP markers increased, being still lower than HIV group. elimination of chronic HCV infection by DAAs allowed an overall improvement of oxidative stress levels and SASP markers to levels like those of the HIV group. No significant differences were observed in telomere shorting between groups after follow-up. Conclusions: As the time since spontaneous resolution of HCV infection increased, patients had an improved senescence profile compared to the HIV control group, with a reduction in oxidative stress and SASP markers. Elimination of chronic HCV infection by DAAs led to a partial improvement of the senescence profile by restoring oxidative stress levels. However, although some SASP markers reached levels like those of the HIV group, others remained altered.