Inside the arteries of a person with HIV, a fuse smolders that does not go out even when the viral load is suppressed. That fuse is chronic inflammation, and a new study shows it is kept alive by a special kind of immune cell that processes vitamin A. Scientists from the Canadian CHACS cohort compared blood from 51 people with HIV on therapy and 63 people without HIV. They found that the former had more monocytes circulating in their blood with high activity of the ALDH enzyme, which converts vitamin A into retinoic acid. Retinoic acid is a powerful regulator of inflammation, and an excess of it can fan the smoldering fire.
The link between ALDH activity and the state of the vessels turned out to be direct. Participants underwent computed tomography of the heart to measure the volume of atherosclerotic plaques. In people with HIV, the frequency of ALDH-positive monocytes correlated with total plaque volume (r=0.44), lipid core volume (r=0.47), and calcium index (r=0.50). In other words, the more cells with active enzyme there were in the blood, the thicker and more dangerous the deposits in the coronary arteries were. In people without HIV, there was no such link.
The smoldering fuse is also fed from the plasma side. Patients with HIV had elevated levels of retinoic acid and of the vitamin A transport protein RBP4. RBP4 also correlated with plaque volume. Curiously, in patients with detectable HIV protein gp120 in their blood, retinoic acid levels were higher, which points to a link with residual viral activity.
The work shows for the first time that in people with HIV on therapy, ALDH enzyme activity in monocytes is associated with subclinical coronary atherosclerosis. This broadens our understanding of the metabolic mechanisms behind cardiovascular risk in HIV. The ALDH/retinoic acid pathway may be a new target for intervention, since standard statin therapy appears not to affect this marker.
The smoldering fuse in the arteries of people with HIV now has a concrete explanation. It is clear that it is sustained by monocytes with high ALDH activity and by an excess of retinoic acid. What remains to be found out is which isoforms of the enzyme are at work in these cells and how to calm them down. Then there will be a chance not just to beat down the flame with statins, but to put out the fuse itself.
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.