HDL in HIV-1 infection: a quality perspective through paraoxonase-1 activities

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina

Cardiovascular disease is highly prevalent on human immunodeficiency virus (HIV)-infected young adults, with serious implications on the choice of the most cardiovascular friendly antiretroviral regimen and its management. Nevirapine (NVP) is an antiretroviral drug that, although associated with hepatotoxicity and skin rash, is currently recognized as a high-density lipoprotein (HDL) booster in HIV-infected patients. This HDL booster effect is even more pronounced than the current available drugs for this purpose. However, besides HDL quantity, its quality is also essential. On this regard, the present study aims to give new insights into the effect of NVP on HDL quality, namely its antioxidant potential, which can be measured through the activities of its associated enzyme, paraoxonase-1 (PON1): paraoxonase (POase), arylesterase (AREase) and lactonase (LACase) activities. The role of PON1 as a protective player against the toxicity inherited to the use of NVP was also explored. Additionally, new methods were developed for the assessment of PON1 AREase and LACase activities. The study protocol received prior approval from the ethics committees of the hospitals and a total of 54 HIV-infected patients were included. The methods herein developed are reliable and suitable for monitoring PON1 AREase and LACase activities in human blood. The negative effect of NVP on PON1 activities is dependent from the formation its phase-I metabolites, especially 12-OH-NVP. The 3-OH-NVP seemed to be the safest metabolite. The current study gives new insights into the players on the mechanism of NVP-toxicity. Moreover, it provides evidence for the development of new NVP or its metabolites analogues, less toxic than NVP, which might in the future have a place in the border of HDL boosters.

Portuguese Foundation for Science and Technology (FCT)- (EXPL/DTP-FTO/0204/2012)