Atherosclerosis and cardiovascular disease are major complications of HIV infection and cannot currently be treated by antiretroviral treatments. The risk of heart disease increases twofold in patients with HIV.
For 15 years, researchers from the George Washington University (GW) have been studying the mechanisms responsible for HIV-associated cardiovascular disease. Recently, the team received more than $3.1 million from the National Institutes of Health to investigate the causes of increased risk of heart disease in HIV-infected subjects.
"We have previously shown that some of the virus-mediated risk may involve dysregulation of high density lipoprotein and reverse cholesterol transport function," said Michael Bukrinsky, MD, PhD, professor of microbiology, immunology, and tropical medicine at the GW School of Medicine and Health Sciences. "It's unclear, however, why these factors do not subside after HIV replication has been minimized to undetectable levels by antiretroviral treatment."
Bukrinsky and his team believe HIV-associated heart disease and atherosclerosis are influenced by a two-hit mechanism. During the early, untreated phase of HIV infection, viral replication alters epigenetic landscape and induces innate memory of myeloid cells increasing their responsiveness to inflammatory stimuli, which persists after the introduction of combined antiretroviral therapy (cART). As a result, low levels of bacterial passage through the incompletely recovered gut mucosa lead to persistent inflammation and cardiovascular disease.
The team members will test their hypothesis using blood and endoscopic samples from an interventional trial. In the trial, a HIV-positive cohort on stable cART will be randomized to receive either placebo or teduglutide, a glucagon-like peptide 2 analog that increases the tightness of gut epithelial barrier and reduces intestinal leakage.
"This study will provide a mechanistic insight into causes of cardiovascular disease risk in HIV-infected patients," said Bukrinsky. "The results will likely provide some guidance on future therapeutic and preventative strategies to reduce heart disease in this population."
The goal for the study is to determine specific viral and host factors driving long-lasting innate immune memory.