Antiretroviral therapy has turned HIV infection into a chronic condition, yet people with HIV on treatment still face an elevated risk of cardiovascular disease. Traditional scales, such as the Framingham risk score, underestimate this risk. The cause is probably chronic inflammation sustained by residual viral activity in reservoirs. The enzyme ALDH (aldehyde dehydrogenase) helps convert vitamin A into retinoic acid, and this pathway is tied both to immune activation in HIV and to the development of atherosclerosis. The study tests whether ALDH activity might be the missing link between HIV and vascular damage.
The analysis included 114 participants from the CHACS cohort: 51 people with HIV on therapy and 63 without HIV. In all of them, the volume of atherosclerotic plaques in the coronary arteries was measured using computed tomography with and without contrast. In frozen blood samples, ALDH activity in immune cells was determined by the ALDEFLUOR assay and flow cytometry. Cells were stained with antibodies against the markers CD14, CD16, CD3, CD4, CD1c, and HLA-DR to separate monocytes, dendritic cells, and T lymphocytes. Plasma concentrations of retinoic acid, retinol-binding protein 4 (RBP4), and chemerin were measured by ELISA. The relationship between cellular and plasma markers and plaque measures was assessed using regression models adjusted for risk factors.
Compared with the control group, people with HIV on therapy had a higher frequency of monocytes with ALDH activity, especially classical ones (CD14+CD16-). These monocytes made up the main pool of ALDH-positive cells. The frequency of ALDH+ monocytes correlated positively with atherosclerotic plaque volume: for total plaque volume, the correlation coefficient was r=0.44 (p=0.044); for lipid core volume, r=0.47 (p=0.031); for the calcium index, r=0.50 (p=0.020). In plasma, patients with HIV had elevated levels of retinoic acid and RBP4, and RBP4 correlated with plaque volume. In patients with detectable HIV gp120 protein in the blood, retinoic acid levels were higher. ALDH activity in classical monocytes correlated with the pericoronary fat attenuation index (pFAI) only in people with HIV.
This work is the first to show that in people with HIV on therapy, the activity of the enzyme ALDH in monocytes is linked to subclinical atherosclerosis of the coronary arteries. This broadens our understanding of the metabolic mechanisms behind cardiovascular risk in HIV. The ALDH/retinoic acid pathway could be a new target for intervention, since standard statin therapy appears not to affect this marker.
It is necessary to determine which specific ALDH isoforms (for example, ALDH1A1, ALDH1A2) are active in monocytes and how they are regulated. It is important to track whether this feature appears before therapy begins or develops during treatment. It would be promising to study whether ALDH+ monocytes enter atherosclerotic plaques and how they behave there.
The results could influence cardiology, infectious disease, and immunology by offering a new biomarker of cardiovascular risk in people with HIV. They also open a direction for developing targeted drugs that affect retinoid metabolism in immune cells.
Conduct longitudinal studies to assess the dynamics of ALDH activity before and after the start of antiretroviral therapy. Identify the specific isoforms of the enzyme and evaluate their link to cardiovascular outcomes.
In HIV immunology, it remains an open question which mechanisms of chronic inflammation lead to accelerated vascular aging. This work ties together previously disconnected observations about the role of vitamin A in the pathogenesis of HIV and atherosclerosis, proposing a specific cellular substrate (monocytes) and an enzymatic pathway (ALDH) for further study. This helps explain why antiviral therapy does not fully eliminate cardiovascular risk.
The enzyme ALDH, which turned out to be linked to atherosclerosis in people with HIV, also handles alcohol metabolism: its inactive form causes facial flushing after drinking alcohol. In this study, its activity was measured in monocytes, not in the liver, where it works on alcohol.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.