Abstract
Although antiretroviral therapy (ART) has resulted in a marked decrease in AIDS-related morbidity and mortality, the therapeutic benefit is often limited by side effects such as metabolic derangement such as lipodystrophy and hyperlipidemia and cardiovascular diseases. These side effects are pervasive in people living with HIV (PLWH). However, the underlying mechanisms are not completely understood. We investigated the effects of ART on cholesterol biosynthesis genes. This is a retrospective analysis of data and specimens collected during a cross-sectional, case-control study of ART-induced toxicity. Cases were HIV treatment-experienced individuals with HIV viral suppression and no diagnosis of ART-associated toxicity (n = 18), and controls were HIV-uninfected individuals (n = 18). The mRNA expressions of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and ATP binding cassette transporter A1 (ABCA1) were significantly upregulated in cases (HIV+) compared to controls (HIV-), as well as the corresponding protein expression level of HMGCR. We observed dysregulation between sterol regulatory element-binding protein 2 (SREBP-2, sensory control) and HMGCR and low-density lipoprotein receptor (LDLR) pathways. Dysregulation of cholesterol biosynthesis genes may predate clinical manifestation of ART-induced lipid abnormalities.
Highlights
Antiretroviral therapy (ART)-associated metabolic derangement and metabolic syndrome (MetS) are more prevalent than ART-associated toxicities such as lactic acidosis, peripheral neuropathies, cardiomyopathies, and pancytopenia [1,2,3,4,5]
We investigated the effect of ART on cholesterol biosynthesis in peripheral blood mononuclear cells (PBMCs) of HIV treatmentexperienced individuals compared to HIV-negative healthy individuals
We interrogated four major pathways genes involved in cholesterol regulation using mRNA and protein expression studies: sensory control, de novo synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMGCR), cholesterol uptake, and efflux (ATP binding cassette transporter A1, ABCA1)
Summary
Antiretroviral therapy (ART)-associated metabolic derangement and metabolic syndrome (MetS) are more prevalent than ART-associated toxicities such as lactic acidosis, peripheral neuropathies, cardiomyopathies, and pancytopenia [1,2,3,4,5]. The high prevalence of MetS and CVDs in PLWH may be due to a complex interplay of HIV infection [11, 12], ART exposure, other viral co-infections [13, 14], and traditional risk factors such as genetic predisposition genetics [15] and lifestyle habits. We hypothesized that ART could perturb cholesterol biosynthesis genes before manifestation of overt signs and symptoms of lipid abnormalities and MetS. We interrogated four major pathways genes involved in cholesterol regulation using mRNA and protein expression studies: sensory control (sensor sterol regulatory element binding protein 2, SREBP-2), de novo synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMGCR), cholesterol uptake (low-density lipoprotein receptor, LDLR), and efflux (ATP binding cassette transporter A1, ABCA1). We measured the expression of AMP-activated protein kinase A1 & B2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
