p53 and p53-related mediators PAI-1 and IGFBP-3 are downregulated in peripheral blood mononuclear cells of HIV-patients exposed to non-nucleoside reverse transcriptase inhibitors

摘要

The improved effectiveness and safety of the combined antiretroviral therapy (cART) has largely diminished mortality and AIDS-defining morbidity of HIV-patients. Nevertheless, chronic age-related diseases in these individuals are more common and their underlying pathogenic mechanisms of these actions seem to involve accelerated aging and enhanced inflammation. The present study explores markers of these processes in a heterogenous Spanish HIV cohort using peripheral blood samples of HIV-patients and matched uninfected controls. We isolated periheral blood mononuclear cells (PBMCs) and i) compared the expression of a panel of 14 genes related to inflammation and senescence in PBMCs of HIV-patients vs matched uninfected controls, ii) analyzed the expression in HIV-patients in association with a number of demographic, biochemical and immunological parameters and iii) in relation with the current cART they received. PBMCs of HIV-patients displayed significantly increased expression of general inflammatory genes (IL6, 1L18 and (XCL10) and this occurs irrespectively of the antiviral therapy they have been receiving. Conversely, levels of senescence-associated genes TP53, SERPINE1 and IGFBP3 were slightly but significantly reduced in patients compared to uninfected matched individuals and this effect is related to NNRTI-containing treatments. The expression of the inflammatory markers 116,1118, IL1B, TNFA, RELA, CCL2, CCL20 and CXCL10 displayed correlation with certain demographic, morbidity- and HIV infection-related parameters. The levels of TP53 mRNA were positively associated only with plasma LDL. Correlation analysis between the expressions of pairs of genes revealed a different pattern between HIV-patients and controls. The diminished expression of TP53 and SERPINE1 in HIV-patients was also observed at a protein level, and the correlation between the two proteins (p53 and PAI1) in patients and controls showed the opposite trend. In conclusion, HIV-patients show dysregulation of p53 and p53-related mediators, a phenomenon which may be of pathophysiological relevance and could be related to the shorter health- and/or life-span observed in these individuals.