HIV-Associated Cardiovascular Disease

Abstract

Chronic HIV infection due to effective antiretroviral treatment has resulted in a broad range of clinical complications, including accelerated heart disease. Individuals with HIV infection have a 1.5 to 2 times higher incidence of cardiovascular diseases than their uninfected counterparts; however, the underlying mechanisms are poorly understood. To explore the link between HIV infection and cardiovascular diseases, we used postmortem human heart tissues obtained from HIV-infected and control uninfected individuals to examine connexin 43 (Cx43) expression and distribution and HIV-associated inflammation. Here, we demonstrate that Cx43 is dysregulated in the hearts of HIV-infected individuals. In all HIV heart samples analyzed, there were areas where Cx43 was overexpressed and found along the lateral membrane of the cardiomyocyte and in the intercalated disks. Areas of HIV tissue with anomalous Cx43 expression and localization also showed calcium overload, sarcofilamental atrophy, and accumulation of collagen. All these changes were independent of viral replication, CD4 counts, inflammation, and type of antiretroviral treatment. Overall, we propose that HIV infection increases Cx43 expression in heart, resulting in tissue damage that likely contributes to the high rates of cardiovascular disease in HIV-infected individuals.

HIV-1 Tat: Role in Bystander Toxicity

“…Furthermore, the exposure of cardiomyocytes to increasing concentration of ATP in vitro caused a significant increase in action potentials, shortening of the time between each contraction and calcium flux in the cells. These findings show that HIV-infection and viral protein exposure lead to multiple damages to the heart and CVD (Prevedel et al, 2017;Tahrir et al, 2018).…”

“…While some of these proteins are anchoring proteins at the plasma membranes, others make intercellular contacts with neighboring cells. One protein family known to be involved in intercellular contacts is the connexins and Cx43, particularly localized mainly at the intercalated discs (Prevedel et al, 2017;Macquart et al, 2018;Schultz et al, 2019). We have shown in a recent publication that Tat induces the upregulation of Cx43 mRNA and proteins in cardiomyocytes and increases in levels of lipofuscin, a known aging heart biomarker, and both observations are seen in non-HIV CVDs as well (Prevedel et al, 2017).…”

“…This finding is unique and explains the large areas compromised by HIV reservoirs even in the current ART era. In conclusion, the combination of direct and indirect effects of Tat leads to neurobehavioral deficits, which are one of the hallmarks of HAND (Prevedel et al, 2017).…”

“…Since HIV-infection is now a chronic disease, several comorbidities like atherosclerosis and cardiovascular disease all related to aging have become common within the population of people with HIV (Gebo et al, 2010;Clifford and Ances, 2013;Fields et al, 2013;Buggey et al, 2019;Ciccarelli et al, 2019). It is known that HIV-infected individuals have 1.5-2 times higher risk of cardiovascular disease (CVD) due to several factors like chronic inflammation, dyslipidemia, lipid abnormalities like low high-density lipoproteins (HDL), increased triglycerides, and prolonged use of ART (Wang et al, 2015;Zungsontiporn et al, 2016;Prevedel et al, 2017;Ciccarelli et al, 2019;Estrada et al, 2019;Heravi et al, 2019;Palma Reis, 2019). HIV-associated CVD is characterized by extensive loss of cardiomyocytes, increase in fibrous tissues and significant infiltration of immune cells to the heart (Prevedel et al, 2017).…”

“…It is known that HIV-infected individuals have 1.5-2 times higher risk of cardiovascular disease (CVD) due to several factors like chronic inflammation, dyslipidemia, lipid abnormalities like low high-density lipoproteins (HDL), increased triglycerides, and prolonged use of ART (Wang et al, 2015;Zungsontiporn et al, 2016;Prevedel et al, 2017;Ciccarelli et al, 2019;Estrada et al, 2019;Heravi et al, 2019;Palma Reis, 2019). HIV-associated CVD is characterized by extensive loss of cardiomyocytes, increase in fibrous tissues and significant infiltration of immune cells to the heart (Prevedel et al, 2017). Most of the studies that have examined the effect of HIV-infection on CVD have shown that there is an increased rate of coronary events and another cardiomyopathy in HIV-infected individuals (Thompson-Paul et al, 2019).…”