Interconnections among inflammation, chronic liver disease and HIVunderstanding the hepatoprotective effects of the antiretroviral drug rilpivirine

Resum

The infection with the human immunodeficiency virus (HIV) remains a very important public health problem. Despite the fact that combined antiretroviral therapy (cART) has largely improved patients’ quality of life, according to many epidemiological studies, these patients are aging earlier and diseases related with age such as cancer, osteoporosis and metabolic diseases are also developed earlier. The responsible mechanisms for these phenomena are still not known, although many studies have suggested a process of premature aging in these patients related with persistent inflammatory state and senescence. Senescence is an irreversible cell cycle arrest driven by various stimuli (telomere shortening, genotoxic stress, oxidative stress, mitogen stimuli, and inflammatory cytokines), and senescent cells, whose proportion increases with age, secrete numerous factors, including inflammatory cytokines, chemokines and their regulators, thus generating low-grade inflammation, considered to be at the core of aging and age-related diseases. In particular, chronic liver disease (CLD) is becoming increasingly prominent in HIV patients. Our recent research has revealed a hepatoprotective effect of the antiretroviral rilpivirine (RPV) in various mouse models of chronic liver injury. However, the mechanisms responsible for these effects are still not fully elucidated. The aims of this doctoral thesis were to investigate the interconnections among inflammation, chronic liver disease and HIV, as well as to explore the molecular mechanisms responsible for the hepatoprotective effects of RPV. First, compared to uninfected matched controls, peripheral blood mononuclear cells (PBMCs) of HIV patients display increased expression of general inflammatory genes, some of which are related to certain demographical, biochemical and immunological parameters and the current cART regimen; while the expression of senescence-associated genes TP53, SERPINE1 and IGFBP3 in HIV patients is diminished, especially in those with non-nucleoside reverse transcriptase inhibitors (NNRTIs)-containing therapies. Second, PBMCs obtained from HIV patients have lower expression of SIRT1, an effect intrinsically linked to the presence of the HIV infection in these individuals as no correlation was found with the patients’ characteristics/variables and cART regimens. Finally, several anti-inflammatory effects that may be relevant for the hepatoprotective function of RPV were described. The expression of CXCL10, a potent pro-inflammatory chemokine, is diminished by RPV. Although the exact molecular mechanisms involved still remain unclear, CXCL10 down-regulation seems to be a result of RPV’s effect on signal transducer and activator of transcription 1 and nuclear factor-kappa B transcription factors. Furthermore, RPV affects the regulation of mitogen activated protein kinase cascade, another potential contributor of the anti-inflammatory function of this antiretroviral drug in the context of CLD.