Researchers at the Medical College of Georgia scientists are investigating an emerging obesity paradox that a new generation of HIV drugs appear to cause weight gain, which appears to limit, rather than increase patients' already significant risk of developing cardiovascular disease. Although these newer generation of HIV drugs have turned the once-lethal infection into a chronic condition, cardiovascular disease has emerged as the leading cause of death in these individuals.
Furthermore, the virus itself and the fact that people are living longer with it, increase their risk of cardiovascular disease, and their weight gain should have a multiplier effect, rather than limit their risk of the nation's number one killer. HIV-positive individuals also appear to have an accelerated disease course with heart attack and heart failure rates even higher than those without the viral infection. However, the first generation of HIV drugs and the uncontrolled virus itself caused often-dramatic weight loss in these patients, which also increased their cardiovascular risk.
"We are really trying to understand this obesity paradox and the mechanisms of atherosclerosis in HIV," said Dr Eric Belin de Chantemele, physiologist in the Vascular Biology Center and Department of Medicine at the Medical College of Georgia at Augusta University.
The investigators are working to find out more about just how the virus contributes to cardiovascular risk; how the commonly used and efficacious antiviral dolutegravir affects weight and other influencers of cardiovascular health; and the ironic 'how' these newer antivirals may limit cardiovascular risk when weight gain itself is a risk factor.
They have evidence that at least one answer to the cardiovascular protection these drugs may afford is the satiety hormone leptin, explained Belin de Chantemele, principal investigator a US$2 million grant (R01 HL147639) from the National Institutes of Health.
"We are thinking leptin could be the protective factor produced by adipose tissu, and this increase in fat mass with the newer antiretroviral agents could potentially protect the blood vessels and limit the development of atherosclerosis," he says.
Too little leptin is vascular damaging, as seen in early patients with HIV at the other end of the spectrum with extreme fat shortage (lipodystrophy). Meanwhile, high leptin levels resulting from obesity are one of the reasons excess weight is a cardiovascular risk factor.
Low leptin signalling leads to increased expression of the Nox1 gene in the lining of blood vessels, which also leads to increased inflammation, superoxide production and generally setting the stage for disease. Without leptin, the blood vessels of patients and mice just cannot relax properly. Leptin therapy in humans with lipodystrophy seems to correct their metabolic problems - and cardiovascular risk - and Belin de Chantemele's team has seen a complete restoration of vascular function in their animal model as well.
However, at high levels, Belin de Chantemele has shown leptin is also bad for the cardiovascular system, increasing factors like levels of the steroid hormone aldosterone, which at high levels contributes to negatives like inflammation and stiff blood vessels.
"Now we are looking at leptin signalling in endothelial cells and looking at whether viral infection impairs vascular leptin signalling and whether this is something that is improved by the new treatments and whether that would limit the development of atherosclerosis," concluded Belin de Chantemele.