Cytomegalovirus and immunological aging: the real driver of HIV and heart disease?

Numerous studies have implicated cytomegalovirus (CMV) as the smoking gun in posttransplant atherosclerosis [1, 2]. Whether CMV is related to the initial development of atherosclerosis and onset of coronary heart disease is still unclear, however. Several epidemiologic studies, along with mechanistic animal studies, suggest some role for CMV in the development of cardiovascular disease [3–6], but the search for a causal link between CMV and heart disease continues today. Research on human immunodeficiency virus (HIV) has made great strides in identifying causal relations between various infections and manifestation of chronic diseases. Ultimately, studies of the impact of HIV on coronary heart disease may be the key to identifying whether CMV is an etiological factor in the development of cardiovascular disease. In this issue of the Journal of Infectious Diseases, Parrinello et al. [7] take us one step closer to understanding the relationship between CMV and development of coronary heart disease. By using data from the Women’s Interagency HIV Study, Parrinello et al. [7] found that higher CMV immunoglobulin G (IgG) levels were not associated with markers of subclinical atherosclerosis among HIV-uninfected women, suggesting that increased antibody levels did not increase the risk of atherosclerosis in their HIV-uninfected subsample. In contrast, HIV-positive women with increased CMV IgG levels were more likely to have carotid artery stiffness. These same individuals did not show greater intima-media thickness nor presence of carotid lesions, indicating that the relationship between CMV IgG levels and markers of cardiovascular disease was specific for carotid artery stiffness in HIV-positive subjects. The relation between increased CMV IgG levels and carotid artery stiffness was consistentacrosstreated/aviremic, treated/ viremic, and untreated HIV-infected groups. However, when examining the association between CMV IgG levels and presence of carotid lesions by treatment/ viremia status groups, Parrinello and colleagues found that CMV IgG levels were associated with presence of carotid artery lesions only among HIV-infected persons who were receiving antiretroviral treatment and were aviremic, after adjustment for age, race, and smoking history. These results suggest that treatment/viremia status modifies the impact of CMV IgG level on carotid lesions. Why would HIV-infected women who were treated and aviremic show the most robust relationship between CMV IgG level and carotid lesions in the study byParrinello and colleagues?One possible answer, as Parrinello et al. [7] suggest, may lie in the magnifying effects of immune restoration inflammatory syndrome from antiretroviral therapy. Immune restoration inflammatory syndrome occurs in up to 25% of HIV-infected persons after the initiation of highly active antiretroviral therapy (HAART), when there is a surge in reconstitution of effector and regulatory T cells [8]. Inflammation and T-cell activation are well established in the etiology of atheroscerlosis among immunocompetent populations [9]. In HIV-positive populations, it is thought that an exacerbated tissue-specific inflammatory immune reaction may occur when CD4+ T cells redistributed from the lymphatic tissue to the periphery are activated by presentation of antigens at sites of preexisting persistent infections, such as CMV [8]. T-cell activation, in concert with decreased ability of regulatory T cells to downregulate the consequent inflammatory response, results in immune reconstitution inflammatory syndrome in individuals who are undergoing HAART [8]. A study by Naeger et al. [10] found that CMV-specific CD8+ T cell responses among HIV-infected individuals was highest among those who had received long-term antiretroviral treatment, supporting a role for modification of the impact of CMV on subclinical atherosclerosis by HIV treatment status. Naeger Received and accepted 12 March 2012; electronically published 5 April 2012. Correspondence: Allison E. Aiello, PhD, MS, Associate Professor of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, MI 48109 ([email protected]). The Journal of Infectious Diseases 2012;205:1772–74 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/infdis/jis288