In this study of a well-characterized group of HIV-infected participants and a demographically similar, high-risk, uninfected comparison group, HIV-infected individuals with higher viral load had higher MCP-1/CCL2 levels, which correlated with greater thoracic aorta atherosclerotic burden. There was also a positive linear relationship between HIV viral load and MCP-1/CCL2, suggesting that the amount of circulating virus may affect MCP-1/CCL2 levels. Although not statistically significant, there was a trend towards a negative correlation of CD4+ cell count with MCP-1/CCL2. Interestingly, even after adjustment for HIV status and viremia, MCP-1/CCL2 remained independently associated with atherosclerotic burden, suggesting that higher MCP-1/CCL2 levels may contribute additional risk for atherosclerosis, even after accounting for the effect of HIV infection, PI use, and traditional cardiovascular risk factors.
Weiss et al reported similar associations between HIV viremia and MCP-1/CCL2, showing higher MCP-1/CCL2 levels in HIV-infected individuals with higher viral loads compared with those with undetectable virus and healthy controls.[21
] Similarly, in a study of 36 HIV-infected subjects, of whom 18 were viremic, investigators reported higher MCP-1/CCL2 mRNA expression and serum levels among viremic compared to aviremic subjects.[22
] Coll et al have reported increased atherosclerosis in HIV-infected patients who have the MCP-1-2518 allele and found a correlation between MCP-1/CCL2 and IMT among HIV- infected patients who also had clinical evidence of lipodystrophy.[23
Our analysis, adjusted for traditional cardiovascular risk factors, revealed greater thoracic aorta VWA and VWT associated with detectable HIV viremia. Having HIV infection, in the absence of detectable viremia, was associated with having greater VWA but not with increased VWT. Of note, corresponding analysis of carotid artery parameters revealed no significant associations with HIV infection or viral load status. It is possible that this reflects a differential impact of HIV infection and associated inflammation on different vascular sites. Both the aorta and the coronary arteries are derived from the embryonic mesoderm, while the carotid arteries develop from the ectoderm.[25
] In addition, the magnitude of shear stress in the aorta differs considerably from that of the carotid arteries, potentially contributing to a differential effect of inflammation on the vascular endothelium in these two locations.[26
] Evidence suggests that the endothelial cell response to inflammatory stimuli is modulated by blood flow, and increased fluid shear stress has been shown to lead to increased MCP-1/CCL2 gene activation. [27
] Our finding of associations of HIV/viral load status and MCP-1/CCL2 concentrations with thoracic aorta but not carotid artery parameters indicates the need for further investigation of mechanisms by which HIV infection promotes atherosclerosis, and perhaps different screening modalities for detecting subclinical vascular disease in HIV-infected individuals.
Other studies of subclinical atherosclerosis in the HIV-infected population have shown variable associations with HIV infection and antiretroviral therapy.[9
] In a prospective cohort study of participants matched for age, sex, race, cigarette smoking, blood pressure and menopausal status, Currier et al reported no association of IMT with HIV infection or PIs, but found instead that age, BMI, and HDL-cholesterol predicted IMT.[9
] In another longitudinal study that assessed both HIV-infected and uninfected participants, Hsue et al reported higher baseline carotid IMT and more rapid 1-year progression among HIV-infected patients versus age-matched controls, but no associations with PIs. In contrast, Johnsen et al found no association of IMT with HIV status, but increased IMT in HIV-infected subjects taking PIs versus those not on PIs.[11
Many of these studies have not, however, included measures of inflammation and none have assessed atherosclerosis in the thoracic aorta. The use of MRI, which allows imaging of the thoracic aorta, is a major strength of our study. Although not in widespread clinical use for cardiovascular risk assessment, MRI is well-validated in cardiovascular research as a sensitive and reliable measure of atherosclerosis.[13
] The fact that MRI allows visualization of the full-thickness of the vessel wall, as opposed to being limited to the intima and media, may be particularly advantageous when assessing atherosclerosis in the setting of HIV-infection. There is evidence suggesting that the mechanism of vascular disease in HIV-infected individuals may differ somewhat from typical atherosclerotic plaque formation. Early in the HIV epidemic, autopsies of young HIV-infected patients found a distinct arteriopathy with lesions intermediate in appearance between typical atherosclerosis and lesions seen with chronic rejection of cardiac transplants.[30
] More recently, Regina et al reported two cases of HIV-infected patients who underwent surgery for carotid artery stenosis, describing extensive inflammatory infiltration of the vascular wall without typical atheromatous plaques.[31
Our study is limited by its cross-sectional design. In addition, the relatively small number of participants with MRI results precludes a more detailed analysis of the impact of viral load and CD4+ cell count within the HIV-infected group. This study does, however, offer the advantage of including an HIV-uninfected comparison group with similar background cardiovascular risk, allowing us to better assess the impact of HIV infection and antiretroviral therapy. Although race/ethnicity was not found to be associated with vessel wall parameters in this study, the majority of participants in our study sample were Black, which may limit ability to generalize our findings to other HIV-infected populations with a different racial/ethnic composition.
In summary, our study finds that higher HIV viral load correlates with higher MCP-1/CCL2 levels, and shows an association of HIV infection and viral load status with atherosclerotic burden in the thoracic aorta. These findings highlight the need for further investigation focusing not only on traditional cardiovascular risk, but also on immunologic factors as potential contributors to atherosclerosis in the HIV-infected population.