Among HIV-infected women, cellular markers of immune activation (defined by presence of CD38 and HLA-DR on circulating CD4+ T cells) were associated with increased carotid artery stiffness. Arterial stiffness was defined as low levels of distensibility and high values of Young’s elastic modulus as measured by B-mode carotid artery ultrasound. The associations between activated CD4+ T cell frequency and vascular stiffness persisted after adjustment for HIV RNA and total peripheral CD4+ T cell count, suggesting that for a given CD4+ T cell count and viral load, higher CD4+ T cell activation was an independent predictor of vascular stiffness. The association between T cell activation and carotid artery stiffness was also shown to be independent of standard vascular risk factors, including plasma lipids, which are often abnormal in HIV-infected individuals. These results agree with prior evidence linking HIV disease with increased vascular stiffness, particularly among individuals with relatively severe immune perturbation. Further, they support the hypothesis that pro-inflammatory populations of T cells may produce functional and/or structural arterial changes in HIV-infected patients with relatively severe damage to the immune system.
HIV infected adults have elevated levels of circulating pro-inflammatory cytokines and a high frequency of circulating CD4+ and CD8+ T cells that express markers of chronic activation, including CD38 and HLA-DR. These T cell abnormalities may be only partially reversed with effective HIV treatment [22
]. While many studies of HIV-infected individuals have shown an association between immunological complications of HIV infection and increased arterial wall thickness [17
], our study supports prior evidence that other types of pathological vascular changes beyond intimal-medial thickening may develop as a result of chronic HIV infection. Vasculitides of various types, which are typically localized to specific vessels in persons at advanced stages of immunocompromise, and which are possibly causally related to T lymphocyte infiltration[27
], are a relatively uncommon complication of HIV infection. More recently, studies have suggested that chronic HIV infection may produce changes in vascular tissues leading to loss of normal arterial elasticity and vasoreactivity. Carotid artery specimens from HIV-infected patients treated surgically for asymptomatic carotid artery stenosis may have degradation of elastic fibers and inflammatory infiltration of the vascular wall [28
]. In addition, uncontrolled HIV replication is associated with reduced brachial artery reactivity, which suggests that impaired endothelial function may also contribute to increased vascular stiffness in HIV-infected persons [29
]. In our data, CD4+CD38+HLA-DR+ T cell frequency was associated with carotid artery distensibility, which is calculated from changes in arterial diameters across the cardiac cycle, as well as with Young’s elastic modulus, which is a different parameter calculated from arterial diameters that also includes standardization to the arterial intima-media thickness. This study is further evidence of a link between HIV disease and vascular pathological changes that may be distinct from atherosclerosis and that occur independently of dyslipidemia and other cardiometabolic risk factors, which were controlled for as potential confounders.
This study has several limitations. First, the cross-sectional nature of the study makes it difficult to establish a cause and effect relationship. Although the most likely explanation for our observations is that inflammation in HIV infected women causes vascular changes, it is conceivable that vascular dysfunction could affect the immune system in some way. It is also possible that unmeasured factors associated with HIV infection may affect both vascular and T cell functions. Second, although the clinical importance of reduced carotid distensibility as well as other non-invasive measures of vascular stiffness has been shown in patient populations with premature vascular disease [1
], the long-term importance of these vascular parameters in predicting future cardiovascular events among HIV-infected adults is unknown. Third, the study was limited to a population which, despite being female and relatively young, had a high burden of cardiovascular risk factors including obesity and smoking. Therefore the results may not be generalizable to men or to populations with different constellations of cardiovascular risk factors. Fourth, we did not have information on regulatory T cells, so were unable to assess the possibility of a confounding effect on the observed associations. Finally, these observations need to be corroborated in larger cohorts. We had relatively limited sample size, so our study only had adequate power to detect a moderate association between activation or senescence and carotid artery stiffness, particularly among HIV-uninfected women.
In summary, our findings suggest that measures of T cell activation, which are known to predict immunologic HIV disease progression [30
], are also associated with increased vascular stiffness among HIV-infected women. Neither cardiometabolic risk factors nor exposure to antiretroviral medications explained the finding between HIV-associated immune perturbation and vascular stiffness measures. This association was also independent of standard clinical measures of HIV disease status including total peripheral CD4+ T cell count and circulating HIV RNA levels. Therefore, our data support the hypothesis that pro-inflammatory populations of T cells may lead to functional or structural changes in the peripheral vasculature. Because effective antiretroviral treatment can reduce these markers of immune perturbation, although not fully reverse them, the findings support the rationale for treating HIV infection to limit immune system damage and also potentially to benefit cardiovascular health.