With prompt diagnosis and the right treatment, people with HIV can live long, healthy lives. In recent years, however, gains in survival among people with HIV have exposed a new concern – an increase in the incidence of early-onset cardiovascular disease associated with long-term HIV.
The reason why cardiovascular disease is likely to develop a full decade earlier in people with HIV than in people without HIV is unclear. But now, with the support of a National Institute on Drug Abuse Avenir Award, part of the National Institutes of Health (NIH) Director's New Innovator (DP2) Award Program, researchers at the Lewis Katz School of Medicine at Temple University hope to gain new insight into the relationship between HIV and heart disease, as well as the effect of substance use on this relationship.
The DP2 award – a first for Temple – is highly competitive, supporting transformative research in high-priority areas designated by the NIH. The funding, $2,377,500 spread over four years, will support studies led by Allison M. Andrews, PhD, Assistant Professor in the Department of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine at Temple University. The research will focus specifically on elucidating the effects of HIV and cocaine use on the bone-marrow blood barrier, a physiological boundary that prevents immature blood cells from escaping the bone marrow.
“We are particularly interested in studying changes in the bone marrow vasculature, microenvironment, and stem cell niche that result from HIV and drugs, such as cocaine,” Dr. Andrews said.
Early-onset cardiovascular disease in people with HIV is associated with increased infiltration of immune cells into the blood vessel wall to form unstable plaques. These immune cells mature from hematopoietic stem cells (HSCs) in the bone marrow niche. It is perhaps no coincidence that the bone marrow also happens to be a reservoir of HIV.
Dr. Andrews and others suspect that HIV somehow alters the local marrow microenvironment and HSC development to ultimately facilitate differentiation of HSCs into activated immune cells. They hypothesize that cocaine, which exacerbates HIV pathology, may amplify the effects of HIV on the bone marrow, or it may enable HSC differentiation via an entirely different mechanism.
Dr. Andrews plans to investigate these ideas through the proposed development of a human bone marrow chip, in which human bone marrow stem cells are embedded in a gel matrix that essentially mimics the 3D nature of bone marrow tissue. Each chip is about the size of a USB flash drive. Using microCT and other advanced imaging techniques, Dr. Andrews and colleagues also plan to map the 3D architecture of the bone marrow vasculature of HIV-infected mice.
“Through these studies, we aim to create a new human 3D tissue-engineered model of the bone marrow vasculature for the study of HIV pathogenesis,” Dr. Andrews added. “The technology is also a promising tool for predictive modeling that could translate clinically into the development of novel strategies for the care of people with HIV who face cardiovascular disease.”