Date Published: April 18, 2019
Publisher: Public Library of Science
Author(s): Hann Low, Anh Hoang, Tatiana Pushkarsky, Larisa Dubrovsky, Elizabeth Dewar, Maria-Silvana Di Yacovo, Nigora Mukhamedova, Lesley Cheng, Catherine Downs, Gary Simon, Maria Saumoy, Andrew F. Hill, Michael L. Fitzgerald, Paul Nestel, Anthony Dart, Jennifer Hoy, Michael Bukrinsky, Dmitri Sviridov, Esther Lutgens.
HIV infection is known to be associated with cardiometabolic abnormalities; here we investigated the progression and causes of these abnormalities. Three groups of participants were recruited: HIV-negative subjects and two groups of treatment-naïve HIV-positive subjects, one group initiating antiretroviral treatment, the other remaining untreated. Intima-media thickness (cIMT) increased in HIV-positive untreated group compared to HIV-negative group, but treatment mitigated the difference. We found no increase in diabetes-related metabolic markers or in the level of inflammation in any of the groups. Total cholesterol, low density lipoprotein cholesterol and apoB levels were lower in HIV-positive groups, while triglyceride and Lp(a) levels did not differ between the groups. We found a statistically significant negative association between viral load and plasma levels of total cholesterol, LDL cholesterol, HDL cholesterol, apoA-I and apoB. HIV-positive patients had hypoalphalipoproteinemia at baseline, and we found a redistribution of sub-populations of high density lipoprotein (HDL) particles with increased proportion of smaller HDL in HIV-positive untreated patients, which may result from increased levels of plasma cholesteryl ester transfer protein in this group. HDL functionality declined in the HIV-negative and HIV-positive untreated groups, but not in HIV-positive treated group. We also found differences between HIV-positive and negative groups in plasma abundance of several microRNAs involved in lipid metabolism. Our data support a hypothesis that cardiometabolic abnormalities in HIV infection are caused by HIV and that antiretroviral treatment itself does not influence key cardiometabolic parameters, but mitigates those affected by HIV.
HIV infection is accompanied by a range of metabolic co-morbidities, with cardiovascular complications being among the most important in terms of morbidity and mortality [1–5]. Initially, cardiovascular co-morbidities of HIV infection were attributed to dyslipidaemia caused by protease inhibitor-containing treatment regimens [6, 7]. However, while the pro-atherogenic regimens were gradually phased out as initial therapy, the cardiovascular and metabolic complications persisted [8, 9]. We have suggested that HIV infection itself can cause atherosclerosis and proposed a mechanism whereby the HIV protein Nef reduces the efficiency of reverse cholesterol transport causing accumulation of cholesterol in macrophages and hypoalphalipoproteinemia [10, 11]. We also demonstrated that extracellular Nef, mimicking Nef released from HIV infected cells into circulation, caused atherosclerosis and dyslipidaemia in vivo in the absence of the infection or any other HIV-related factors . While experimental findings point to the important role of HIV itself in the pathogenesis of cardiovascular and metabolic co-morbidities of HIV infection, separation between the effects of HIV and of antiretroviral treatment in the clinical setting is difficult as the overwhelming majority of HIV-positive patients now commence antiretroviral treatment immediately after diagnosis. Furthermore, HIV-positive patients often have overrepresented conventional cardiovascular risk factors, such as high rates of smoking, which may also contribute to the elevated cardiovascular risk . These factors complicate investigation of the causes, pathogenic mechanisms and progression of HIV-associated cardiometabolic co-morbidities.
In this study, we investigated metabolic dysfunction and atherosclerosis in people newly diagnosed with HIV infection who commenced antiretroviral therapy (ART) or remained untreated for 3 years. This study was performed prior to the recommendation that all HIV-positive patients commence ART immediately after HIV diagnosis regardless of CD4 cell count. A significant rise in cIMT was observed in untreated HIV-infected patients after 2 years. In uninfected group, there was a modest rise in cIMT after 1 year, which did not progress further, and in treated patients a modest rise was seen after 3 years. This finding indicates that progression of atherosclerosis, as assessed by changes in cIMT, seen in HIV-positive patients, was mitigated by ART. This is consistent with a suggestion that HIV infection itself, rather than side-effects of ART, is a major cause of elevated cardiovascular risk in HIV-positive patients [10, 30]. It is also consistent with the view that controlling HIV disease with modern ART regimens effectively restrains progression of atherosclerosis without bringing an additional iatrogenic cardiovascular risk. The changes in atherosclerosis progression took at least two years to manifest, consistent with no change in cIMT after one year of follow up reported in our previous study . Differences in lifestyle factors between HIV-negative and treated HIV-positive subjects apparently did not contribute significantly to the progression of atherosclerosis, a finding consistent with our previous report . Recognizing limitations of IMT as a predictor of future cardiovascular events , our findings tentatively support a hypothesis that HIV infection contributes to the pathogenesis of atherosclerosis, as proposed in a number of cross-sectional and prospective studies [2, 5, 14–16, 20–22] and confirmed in recently published meta-analysis .