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T cell activation predicts carotid artery stiffness among HIV-infected women
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8 March 2011
"Prior evidence suggests that patients infected with HIV may have increased risk of clinical cardiovascular events as well as subclinical structural and functional vascular changes. Among a cohort of HIV-infected women, we studied the association of carotid artery stiffness with expression of markers of T cell activation (CD38+HLA-DR+). Our findings suggest that activation of CD4+ T cells is associated with increased vascular stiffness among HIV-infected women. These findings are important because these immunologic perturbations almost universally affect patients with advanced HIV disease, and may also be elevated in those on effective antiretroviral therapy."
Robert C. Kaplana, Corresponding Author Contact Information, E-mail The Corresponding Author, Elizabeth Sinclairb, Alan L. Landayc, Nell Lurainc, A. Richey Sharrettd, Stephen J. Ganged, Xiaonan Xuea, Christina M. Parrinelloa, Peter Huntb, Steven G. Deeksb and Howard N. Hodise
a Department of Epidemiology and Population Health, Albert Einstein College of Medicine, United States
b Division of Experimental Medicine, University of California-San Francisco, United States
c Rush University Medical Center, United States
d Johns Hopkins Bloomberg School of Public Health, United States
e Atherosclerosis Research Unit, University of Southern California, United States
Abstract
Objectives
HIV disease is associated with increased arterial stiffness, which may be related to inflammation provoked by HIV-related immune perturbation. We assessed the association of T cell markers of immune activation and immunosenescence with carotid artery stiffness among HIV-infected women.
Methods
Among 114 HIV-infected and 43 HIV-uninfected women, we measured CD4+ and CD8+ T cell populations expressing activation (CD38+HLA-DR+) and senescence (CD28-CD57+) markers. We then related these measures of immune status with parameters of carotid artery stiffness, including decreased distensibility, and increased Young's elastic modulus, as assessed by B-mode ultrasound.
Results
HIV infection was associated with increased CD4+ T cell activation, CD8+ T cell activation and CD8+ T cell senescence. Among HIV-infected women, adjusted for age, HIV medications, and vascular risk factors, higher CD4+CD38+HLA-DR+ T cell frequency was associated with decreased carotid artery distensibility (ß = -2.00, 95% confidence interval [CI] = -3.86, -0.14, P = 0.04) and increased Young's modulus (ß = 1.00, 95% CI = 0.03, 1.97, P = 0.04). These associations were affected little by further adjustment for CD4+ T cell count and viral load. Among HIV-infected women, higher frequencies of immunosenescent T cells, including CD4+CD28-CD57+ and CD8+CD28-CD57+ T cells, were also associated with decreased arterial distensibility. Among HIV-uninfected women, frequencies of activated or senescent T cells were not significantly associated with measures of carotid stiffness.
Discussion
T cell activation and senescence are associated with arterial stiffness, suggesting that pro-inflammatory populations of T cells may produce functional or structural vascular changes in HIV-infected women.
Arterial stiffness is often increased in the presence of established cardiovascular risk factors including aging, diabetes, hypertension and chronic kidney disease [1]. HIV infection, particularly when associated with severe immunodeficiency, has recently been added to the list of conditions known to be associated with vascular stiffening in adults [2], [3], [4] and [5]. This effect of HIV infection is evident even in HIV-infected children, who have decreased carotid artery distensibility without concomitant increases in carotid artery wall thickness [6].
Many of the diseases that produce premature arterial stiffness, including HIV infection and Kawasaki disease [7], are inflammatory conditions. Markers of inflammation have been correlated with the degree of vascular stiffness in various populations including stroke survivors [8], patients with renal disease [9] and obstructive sleep apnea [10], and apparently healthy adults [11] and [12]. We hypothesized that increased arterial stiffness in patients infected with HIV may be associated with pro-inflammatory T cell subsets, including T cells expressing markers of activation and senescence. In the setting of HIV infection, activated T cells are abundant and are thought to be an important source of inflammation. Activated CD4+ T cells are known to localize to arterial tissues in regions affected by vascular disease [13] and may in turn produce inflammatory mediators which activate matrix-degrading enzymes such as matrix metalloproteinase-1 (MMP-1), MMP-3, and MMP-9 [14], [15] and [16]. In HIV-infected persons, senescence markers are found on a large frequency of CD8+ T cells, and to a lesser extent on CD4+ T cells. Senescent T cells are apoptosis-resistant and, like activated T cells, may secrete pro-inflammatory mediators. We recently showed that among HIV-infected patients, higher frequencies of T cells expressing markers of activation (CD38, HLA-DR) and senescence (presence of CD57, absence of CD28) were associated with greater arterial wall thickness [17]. In the present study, we examined whether increased carotid artery stiffness, which we assessed from measurements of arterial diameters obtained by B-mode ultrasound, was also related to T cell activation and senescence.
Results
Among HIV-infected women, 36% were not currently receiving antiretroviral treatment, 39% were treated and had detectable viremia, and 25% were treated and did not have detectable HIV. As previously described [17], HIV-infected women had higher frequencies of activated CD4+ and CD8+ T cells, and higher frequency of senescent CD8+ T cells, as compared with HIV-uninfected women (Table 1). Other HIV-related and cardiovascular variables appear in Table 1. Pearson correlations between carotid artery distensibility and Young's elastic modulus were in the range of r = -0.75 to -0.80 (Fig. 1).
Correlation among immune status, C-reactive protein level, and HIV RNA
Low CD4+ T cell count was associated with increased activation of CD4+ T cells (r = -0.72, P < 0.0001), and to a lesser extent increased activation of CD8+ T cells (r = -0.32, P < 0.01) (Table 2). HIV RNA was positively correlated with CD4+ and CD8+ T cell activation (r = 0.44-0.46, P < 0.0001). C-reactive protein levels had no significant correlation with T cell parameters or HIV RNA.
T cell activation and senescence as predictors of carotid artery stiffness
Among HIV-infected women, higher frequencies of CD4+CD38+HLA-DR+ T cells were associated with decreased carotid artery distensibility and with increased Young's elastic modulus (Fig. 2), and these associations were statistically significant (P = 0.04) after adjustment for age and other cardiovascular risk factors (Table 3). In subsequent models that also included HIV RNA and CD4+ T cell count as adjustment variables, the point estimates of association were almost completely unchanged, although confidence intervals and P-values were slightly larger (Table 4). In the HIV-infected group, women with higher frequencies of CD4+CD28-CD57+ and CD8+CD28-CD57+ T cells had reduced carotid artery distensibility after adjustment for cardiovascular and HIV-related variables (Table 4). However, significant associations between T cell senescence markers and arterial stiffness were not seen when Young's modulus rather than distensibility was defined as the outcome variable ([Table 3] and [Table 4]).
We then examined the association of carotid artery stiffness with frequencies of activated CD4+ T cells and senescent CD4+ T cells when examined jointly in the same model. Mean carotid artery distensibility was 16.6 x 10-6 m2/N among HIV-infected women who were above the median value of both CD4+CD38+HLA-DR+ T cell frequency and CD4+CD28-CD57+ T cell frequency. In comparison, mean distensibility was in the range of 19.1-19.6 x 10-6 m2/N among the groups that only had CD4+CD38+HLA-DR+ T cell frequency above the median, that only had CD4+CD28-CD57+ T cell frequency above the median, or that had neither above the median. Adjusted for age and cardiovascular risk factors, comparing HIV-infected women with both CD4+ T cell activation and CD4+ T cell senescence above the median values versus those with both CD4+ T cell activation and senescence below the median values, the adjusted difference in distensibility was -2.5 x 10-6 m2/N (95% confidence interval -6.4 x 10-6 to 1.3 x 10-6, P = 0.21).
Adjustment for C-reactive protein had minimal effect on the associations of T cell activation and senescence markers with carotid artery stiffness, nor was C-reactive protein level a significant predictor of carotid artery distensibility or Young's modulus (data not shown).
Among HIV-uninfected women, no significant associations of T cell activation or senescence with carotid distensibility or Young's modulus were observed (data not shown).
Discussion
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], [23] and [24]. While many studies of HIV-infected individuals have shown an association between immunological complications of HIV infection and increased arterial wall thickness [17], [25] and [26], 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] J.V Giorgi, L.E. Hultin and J.A. McKeating et al., Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage, J Infect Dis 179 (1999), pp. 859-870. View Record in Scopus | Cited By in Scopus (388)[30] and [31], 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.
Statement of conclusions
Prior evidence suggests that patients infected with HIV may have increased risk of clinical cardiovascular events as well as subclinical structural and functional vascular changes. Among a cohort of HIV-infected women, we studied the association of carotid artery stiffness with expression of markers of T cell activation (CD38+HLA-DR+). Our findings suggest that activation of CD4+ T cells is associated with increased vascular stiffness among HIV-infected women. These findings are important because these immunologic perturbations almost universally affect patients with advanced HIV disease, and may also be elevated in those on effective antiretroviral therapy.
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