Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral 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 Aleksandra Gruevska a,b,1 , Angela B. Moragrega a,b,1 , Maria J. Galindo c , Juan V. Esplugues a,b,d , Ana Blas-Garcia b,d,e,2 , Nadezda Apostolova a,b,d,∗,2 a Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain b FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain c Unidad de Enfermedades Infecciosas – Medicina Interna, Hospital Clínico Universitario de Valencia, Spain d CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Spain e Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain ARTICLE INFO Keywords: Antiretroviral drugs HIV Aging Infammation p53 Senescence NNRTI ABSTRACT The improved efectiveness and safety of the combined antiretroviral therapy (cART) has largely diminished mortality and AIDS-defning morbidity of HIV-patients. Nevertheless, chronic age-related diseases in these in- dividuals are more common and their underlying pathogenic mechanisms of these actions seem to involve ac- celerated aging and enhanced infammation. The present study explores markers of these processes in a het- erogenous 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 infammation 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 sig- nifcantly increased expression of general infammatory genes (IL6, IL18 and CXCL10) and this occurs irre- spectively of the antiviral therapy they have been receiving. Conversely, levels of senescence-associated genes TP53, SERPINE1 and IGFBP3 were slightly but signifcantly reduced in patients compared to uninfected matched individuals and this efect is related to NNRTI-containing treatments. The expression of the infammatory markers IL6, IL18, 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 diferent 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 phe- nomenon which may be of pathophysiological relevance and could be related to the shorter health- and/or life- span observed in these individuals. 1. Introduction Currently 40–60% of adults living with HIV in high-income coun- tries are ≥50 years old mainly due to the efectiveness of the available anti-HIV treatments. Nevertheless, while combined antiretroviral therapy (cART) has reduced the likelihood of AIDS-defning illnesses, non-AIDS conditions linked with aging (chronic cardiovascular, lung or liver disease, certain cancers and neurocognitive disorders) are more https://doi.org/10.1016/j.antiviral.2020.104784 Received 28 December 2019; Received in revised form 22 March 2020; Accepted 23 March 2020 Abbreviations: AIDS, acquired immunodefciency syndrome; BMI, body mass index; cART, combined antiretroviral therapy; CMV, cytomegalovirus; CVR, cardio- vascular risk; DM, diabetes mellitus; HIV, human immunodefciency virus; II, integrase inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non- nucleoside reverse transcriptase inhibitors; PBMCs, peripheral blood mononuclear cells; PI, protease inhibitors ∗ Corresponding author. Avda Blasco Ibañez n.15-17, 46010, Valencia, Spain. E-mail address: nadezda.apostolova@uv.es (N. Apostolova). 1 these authors have contributed equally. 2 these authors have contributed equally. Antiviral Research 178 (2020) 104784 Available online 06 April 2020 0166-3542/ © 2020 Elsevier B.V. All rights reserved. T