Provocative findings from a US-Australian research group may force the HIV field to revise its understanding of cardiovascular disease risk in people on antiretroviral treatment. The group has found that HIV’s nef protein causes macrophages, the immune system cells implicated in the development of atherosclerosis, to accumulate more cholesterol, and to develop rapidly into cells of a type found in atherosclerotic plaques, the accumulations of fatty cells and debris which cause arteries to narrow and the walls to harden.
Several large studies have now demonstrated an increased risk of cardiovascular disease in people receiving antiretroviral treatment, while other studies have shown changes in lipid metabolism in people infected with HIV even before treatment starts – in particular, a decline in HDL cholesterol that may not be ameliorated by antiretroviral therapy.
However, little is known about how HIV affects lipid metabolism, so a team from George Washington University in Washington DC, the University of New South Wales in Sydney and the Baker Heart Institute in Melbourne set out to investigate the effects of HIV infection on cholesterol in macrophages, a key cell infected by the virus and also a key cell in the development of atherosclerosis.
The researchers hypothesised that since HIV needs cholesterol for HIV assembly and budding, and in order to infect new cells, it must have evolved some means of regulating cholesterol availability within cells and for delivering cholesterol to the viral assembly site within cells. If so, might this mechanism also have a wider impact on cholesterol traffic in and out of macrophages, and so affect the propensity of macrophages to turn into foam cells, the form of macrophages found in atherosclerotic plaques?
They found that HIV’s nef protein down-regulates the activity of ABCA-1, a transporter which contributes towards the transformation of apolipoprotein-A-1 into HDL cholesterol in macrophages. Expression of the transporter was inversely correlated with levels of HIV replication within macrophages, and was not diminished when cells were infected with nef-deficient HIV.
They also found that when macrophages were infected with HIV, they accumulated large volumes of cholesterol. This did not happen when nef-deleted HIV was used in the experiments, further confirming the role of this protein in lipid disorders.
Atherosclerotic plaques obtained from HIV-positive patients receiving antiretroviral therapy were also examined, and found to contain macrophages infected with HIV, suggesting that these infected macrophages were involved in the development of the plaques.
Finally, they observed that when HIV-infected cells were treated with an agent that increased cholesterol removal, or efflux, by upregulating the activity of ABCA-1 (an LXR agonist), the infectivity of HIV was reduced by around 80% when compared with untreated cells, demonstrating the importance of cholesterol to the viral life-cycle. The researchers suggest that drugs which increase cholesterol efflux may have a role in HIV treatment.
In an editorial accompanying the publication in PLoS Medicine, Dr Andrew Carr of St Vincent’s Hospital, Sydney, and Dr Daniel Ory of Washington University School of Medicine, St Louis, point out that mutations in ABCA-1 are known to cause Tangier disease, which is associated with low HDL cholesterol and accelerated atherosclerosis.
“The findings provide a possible mechanism to explain low HDL cholesterol in HIV infection and increased cardiovascular risk in HIV-infected adults,” they say. But they point out that if this were the primary mechanism, HDL cholesterol would be expected to fall soon after primary infection, return to pre-infection levels with effective antiretroviral therapy and be inversely proportionate to HIV viral load reductions. Findings are inconsistent in respect of each of these relationships however.
Nevertheless they comment: “The data support the shift away from a paradigm of delaying or stopping ART to reduce the risk of cardiovascular disease. The data also emphasise the need for clinicians to consider all the metabolic effects (in particular the ratio of total cholesterol to HDL) of each antiretroviral drug, not just total cholesterol levels, in the management of cardiovascular risk in HIV-infected adults.