Citation: Bukrinsky M, Sviridov D (2007) HIV and Cardiovascular Disease: Contribution of HIV-Infected Macrophages to Development of Atherosclerosis. PLoS Med 4(1): e43. https://doi.org/10.1371/journal.pmed.0040043
Published: January 30, 2007
Copyright: © 2007 Bukrinsky and Sviridov. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this article.
Competing interests: The authors have declared that no competing interests exist.
In their Perspective published in PLoS Medicine , Carr and Ory provide a fair review of our recent paper in PLoS Biology . 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 , 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 . 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 , 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 , 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 . 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 , 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 .
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.
- 1. Carr A, Ory D (2006) Does HIV cause cardiovascular disease? PLoS Med 3: e496.A. CarrD. Ory2006Does HIV cause cardiovascular disease?PLoS Med3e496
- 2. Mujawar Z, Rose H, Morrow MP, Pushkarsky T, Dubrovsky L, et al. (2006) Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol 4: e365.Z. MujawarH. RoseMP MorrowT. PushkarskyL. Dubrovsky2006Human immunodeficiency virus impairs reverse cholesterol transport from macrophages.PLoS Biol4e365
- 3. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, et al. (1992) Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 74: 1045–1052.C. GrunfeldM. PangW. DoerrlerJK ShigenagaP. Jensen1992Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.J Clin Endocrinol Metab7410451052
- 4. van der Valk M, Kastelein JJ, Murphy RL, van Leth F, Katlama C, et al. (2001) Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 15: 2407–2414.M. van der ValkJJ KasteleinRL MurphyF. van LethC. Katlama2001Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile.AIDS1524072414
- 5. Crook MA, Mir N (1999) Abnormal lipids and the acquired immunodeficiency syndrome: Is there a problem and what should we do about it? Int J STD AIDS 10: 353–356.MA CrookN. Mir1999Abnormal lipids and the acquired immunodeficiency syndrome: Is there a problem and what should we do about it?Int J STD AIDS10353356
- 6. Singaraja RR, van Eck M, Bissada N, Zimetti F, Collins HL, et al. (2006) Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo. Circulation 114: 1301–1309.RR SingarajaM. van EckN. BissadaF. ZimettiHL Collins2006Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo.Circulation11413011309
- 7. Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, et al. (2002) Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol 22: 630–637.RJ AielloD. BreesPA BourassaL. RoyerS. Lindsey2002Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages.Arterioscler Thromb Vasc Biol22630637
- 8. Pomerantz RJ (2003) Reservoirs, sanctuaries, and residual disease: The hiding spots of HIV-1. HIV Clin Trials 4: 137–143.RJ Pomerantz2003Reservoirs, sanctuaries, and residual disease: The hiding spots of HIV-1.HIV Clin Trials4137143
- 9. Stewart S, Wilkinson D, Becker A, Askew D, Ntyintyane L, et al. (2006) Mapping the emergence of heart disease in a black, urban population in Africa: The Heart of Soweto Study. Int J Cardiol 108: 101–108.S. StewartD. WilkinsonA. BeckerD. AskewL. Ntyintyane2006Mapping the emergence of heart disease in a black, urban population in Africa: The Heart of Soweto Study.Int J Cardiol108101108