In their Perspective published in PLoS Medicine [1], Carr and Ory provide a fair review of our recent paper in PLoS Biology [2]. However, we believe their commentary puts too much emphasis on the role of low high-density lipoprotein (HDL) cholesterol levels as a cause of atherosclerosis in HIV-infected patients. While HDL cholesterol levels are reduced in untreated HIV infection [3], and defects in reverse cholesterol transport (RCT) that we reported may well be a contributing factor to this abnormality, initiation of antiretroviral therapy restores HDL levels [4]. Although the development of dyslipidemia with prolonged use of anti-HIV drugs again lowers HDL cholesterol and in addition raises very low-density lipoprotein and low-density lipoprotein levels [5], it is unlikely that HIV infection contributes significantly to these effects. Indeed, most HDL comes from the liver and intestine, which are responsible for maintaining plasma HDL levels [6], but neither hepatocytes nor enterocytes are infected by HIV. Also, the number of HIV-infected cells in treated patients is relatively low to account for any general changes in concentration of plasma lipoproteins.

We suggest a different model that provides a simple connection between HIV-induced impairment of the cellular step of RCT and pathogenesis of atherosclerosis. We propose that RCT-defective HIV-infected macrophages contribute to development of atherosclerosis in HIV patients by converting into foam cells and initiating plaque formation in the vessel wall. Indeed, specific inactivation of ABCA1 in macrophages has been shown to induce atherosclerosis in a mouse model independently from plasma HDL level [7]. Plaque formation through this mechanism can begin even on the background of normal HDL but would be greatly accelerated by dyslipidemia, a condition observed in HIV patients treated with antiretroviral therapy. Given that even fully suppressive HAART (highly active antiretroviral therapy) does not eliminate long-lived productive reservoirs of the virus and that macrophages are a likely potential component of these reservoirs [8], long-lived HIV-infected macrophages may contribute to atherosclerotic plaque formation long after initiation of HAART. Consistent with this hypothesis, it was found that the majority of cardiovascular events in HIV-infected patients are “one plaque” events [9].

Therefore, several lines of evidence indirectly implicate HIV-infected macrophages in the pathogenesis of atherosclerosis in HIV patients. Future studies will determine the role of HIV-induced RCT impairment in this process and are expected to provide an understanding of the connection between HIV infection and atherosclerosis and to identify novel treatment targets for both diseases.