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Brain large artery inflammation associated with HIV and large artery remodeling
 
 
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"In spite of great advances in the management of HIV infection, vascular disease has emerged as a major cause of morbidity and mortality in the treated HIV population, with stroke among the most worrisome of cerebrovascular complications......Stroke and HIV-associated neurocognitive disorders, however, have continued to afflict those with HIV despite the use of cART.....We present here results from a sample of autopsied brains from HIV+ and HIV- individuals. In this sample, we tested the hypothesis that brain arteries from HIV+ cases have a greater degree of inflammation than brain arteries from HIV- cases, and that inflammation is associated with brain arterial remodeling......brain arteries in HIV+ cases appeared to have an enhanced susceptibility to develop adventitial inflammation compared with HIV- cases, independent of atherosclerosis or intimal inflammation......We report here an association between HIV infection and inflammation in brain large arteries. Although intimal inflammation is closely linked to ILAA independent of HIV, adventitial inflammation was strongly associated with HIV and it was predictive of a thinner media and dolichoectasia. These results support a role for adventitia inflammation in the pathogenesis of HIV vasculopathy. Further understanding of the drivers of arterial inflammation may offer the opportunity to conceive novel therapies that may tackle the rising incidence of cerebrovascular disease in the HIV population."
 
"The arterial inflammatory process in HIV appears to be systemic, as evidenced by a significant increase in serum markers of endothelial activation in patients with HIV compared with uninfected controls, only partially blunted after initiation of cART [37]. Whether the antigenic stimulus for intimal inflammation differs by HIV status is still a matter of research, but understanding the mechanisms of ILAA is important, as ILAA accounts for up to 42% of strokes in HIV patients."
 
Adventitia is the outermost connective tissue covering of an organ, vessel, or other structure.[1] It is also called the tunica adventitia[1] or the tunica externa. For example, the connective tissue that surrounds an artery is called the tunica externa because it is considered extraneous to the artery.........https://en.wikipedia.org/wiki/Adventitia......Conventional views of the tunica adventitia as a poorly organized layer of vessel wall composed of fibroblasts, connective tissue, and perivascular nerves are undergoing revision. Recent studies suggest that the adventitia has properties of a stem/progenitor cell niche in the artery wall that may be poised to respond to arterial injury. It is also a major site of immune surveillance and inflammatory cell trafficking and harbors a dynamic microvasculature, the vasa vasorum, that maintains the medial layer and provides an important gateway for macrophage and leukocyte migration into the intima. In addition, the adventitia is in contact with tissue that surrounds the vessel and may actively participate in exchange of signals and cells between the vessel wall and the tissue in which it resides. This brief review highlights recent advances in our understanding of the adventitia and its resident progenitor cells and discusses progress toward an integrated view of adventitial function in vascular development, repair, and disease.....http://atvb.ahajournals.org/content/31/7/1530.full
 
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Brain large artery inflammation associated with HIV and large artery remodeling
 
AIDS Jan 28 2016
 
Gutierrez, Josea; Menshawy, Khaledb; Gonzalez, Marcoc; Goldman, Jamesd; Elkind, Mitchell S.V.a,e; Marshall, Randolpha; Morgello, Susanf
aDepartment of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, USAbAlexandria Faculty of Medicine, EgyptcDepartment of Neurological Sciences, University of Nebraska Medical Center, NebraskadDepartment of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University Medical CentereDepartment of Epidemiology, Mailman School of Public Health, Columbia University Medical CenterfDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA.
 
Abstract
 
Objective:
To test the hypothesis that brain arteries from HIV+ cases have a greater degree of inflammation than brain arteries from HIV- cases, and that inflammation is associated with brain arterial remodeling.
 
Design: Case-control study, cross-sectional.
 
Methods: Brain arteries from 162 autopsy cases (84 with HIV) were systematically analyzed for thickness of the intima, media, and adventitia, and atherosclerosis and dolichoectasia. Inflammation was assessed with CD68+ immunohistochemistry, and measured with a semiquantitative score reflecting the number and location (i.e., arterial layer) of activated macrophages infiltrating the arterial wall. Latent varicella zoster virus (VZV) was assessed with anti-VZV gene 63 product immunohistochemistry. Demographic and clinical variables were available in all cases, and longitudinal data about CD4+ cell counts were available among cases with HIV. Multilevel generalized linear models were used to test the association between inflammation and HIV.
 
Results: Arteries from HIV+ cases had a higher inflammation score (B = 0.36, P = 0.05) compared with arteries from HIV- cases, although the association was attenuated after controlling for demographic variables, vascular risk factors, and latent VZV (B = 0.20, P = 0.18). Although intimal inflammation was similar in cases with and without HIV, adventitial inflammation was associated with HIV. Intimal inflammation was associated with intracranial atherosclerosis independent of HIV status, but adventitial inflammation was associated with HIV-associated dolichoectasia in arteries with a thin media Conclusions: Adventitial inflammation is associated with HIV and dolichoectasia independent of intracranial atherosclerosis. This suggests that differential inflammatory responses may play a role in intracranial atherosclerosis and dolichoectasia.
 
Introduction
 
Infection with HIV has evolved from a nearly universal fatal disease to a chronic infection with the administration of combined antiretroviral therapy (cART). In spite of great advances in the management of HIV infection, vascular disease has emerged as a major cause of morbidity and mortality in the treated HIV population, with stroke among the most worrisome of cerebrovascular complications [1-3]. Early in the HIV pandemic, neurological complications and brain damage were noted in the majority of individuals who died with profound immunosuppression [4,5]. With the advent of cART, the progressive restoration of the immune system led to a sharp decrease in the rates of death because of opportunistic infections and neoplasia [3,4]. Stroke and HIV-associated neurocognitive disorders, however, have continued to afflict those with HIV despite the use of cART [2,6]. Some reports even suggest that the stroke incidence among those with HIV is higher than in uninfected control samples [7]. Although clinical guidelines for treating HIV emphasize the value of CD4+ cell counts as markers of restored immunity, a growing body of evidence suggests that HIV infection has profound effects on the host immune system leading to chronic immune activation [8]. The central nervous system, although selectively impermeable to most blood elements, may be rendered vulnerable to systemic inflammation and may alter the course of cerebrovascular disease [9-11]. Aortic inflammation has been reported in individuals with HIV with normalized CD4+ cell counts while on cART, and the inflammation correlated with the atherosclerotic burden [12]. Inflammatory cells are frequently noted in arterial specimens from patients with 'HIV vasculopathy' [13,14]. Few studies have systematically assessed for the presence of inflammatory cells in brain arteries. Because the brain arteries do not remodel outward in the same way as systemic arteries do in the setting of atherosclerosis [15], determining whether inflammation in brain arteries may play a role in brain arterial remodeling may lead to a better understanding of the pathophysiology of stroke in the HIV population.
 
We present here results from a sample of autopsied brains from HIV+ and HIV- individuals. In this sample, we tested the hypothesis that brain arteries from HIV+ cases have a greater degree of inflammation than brain arteries from HIV- cases, and that inflammation is associated with brain arterial remodeling.
 
Results
 
Sample studied

 
Brain arteries from 162 autopsied cases were included in this study, and 84 had HIV. The average number of arteries per case was 6.7 (range 3-11) in HIV+ cases and 5.8 (range 2-9) in HIV- (P = 0.001). The demographic and clinical variables of cases included in this sample are presented in Table 1. In multivariable logistic regression analysis, cases with HIV were more likely to be non-Hispanic blacks (OR 4.3, 1.4-13.7), to be smokers (OR 2.93, 1.2-7.2), and to have used cocaine (OR 5.2, 1.7-15.8). None of the other variables used in Table 1 remained significant.
 
HIV status and brain arterial inflammation
 
A total of 1018 segments of large brain arteries were studied. In arteries from HIV- cases, 174/452 (38%) had evidence of inflammation (i.e. inflammation score ≥1): 124 of 152 (27%) in the intima, 18 of 452 (4%) in the media, and 98 of 452 (22%) in the adventitia. In arteries from HIV+ cases, 308 of 566 (54%) had evidence of inflammation: 135 of 566 (24%) in the intima, 25 of 566 (4%) in the media, and 250 of 566 (44%) in the adventitia. In the whole sample, inflammation in the media was observed accompanying intima inflammation in 39 of 43 of the cases; only four of 43 arteries had media inflammation without intima inflammation. The prevalence of latent VZV infection was 55% in HIV+ cases versus 60% in HIV- cases (P = 0.11). In univariate analysis, arteries from HIV+ cases had a higher inflammatory score (B = 0.36, P = 0.05) compared with arteries from HIV- cases. After adjusting for demographic variables, vascular risk factors, and latent VZV, the association between inflammation score and HIV was no longer statistically significant (B = 0.20, P = 0.18).
 
The localization of inflammation in the arterial wall, however, varied significantly by HIV status (Fig. 2). Compared with arteries from HIV- cases, arteries from HIV+ cases were more likely to have adventitial inflammation (B = 0.80, P < 0.001). Adjusting for demographic, vascular risk factors, and latent VZV (B = 0.70, P = 0.01), or categorizing inflammation as 'predominantly adventitial' (B = 1.05, P = 0.003) did not eliminate the association. There were no significant differences in the distribution of intima (B = -0.16, P = 0.46) or media inflammation (B = -0.14, P = 0.78) by HIV status.
 
Brain arterial remodeling and brain arterial inflammation
 
In univariate analysis, arterial inflammation was associated with smaller LWR (B = -0.33, P = <0.001). This association was enhanced when the inflammation was restricted to the intima (B = -0.88, P = <0.001). Inflammation in the adventitia was associated with larger LWR (B = 0.21, P = 0.02). We did not find evidence of a nonlinear association between inflammation and LWR (data not shown).
 
In adjusted models, arterial inflammation was associated with smaller LWR and with ILAA. These associations were stronger when the inflammation was predominantly localized to the intima. These associations varied little by HIV status (Table 2). The predictors for media thickness, however, varied by HIV status. Although intima inflammation was associated with a thinner media in HIV- cases only (B = -0.13, P < 0.001), adventitial inflammation was associated with a thinner media in HIV+ cases (B = -0.09, P = 0.05), but not in those without HIV. Adventitia inflammation was not associated with dolichoectasia or with a higher LWR, but adventitial inflammation in arteries with a media thickness in the 5th percentile was associated with dolichoectasia (B = 0.84, P = 0.02) in HIV+ cases but not in HIV- cases (B = -19.9, P = 0.99).
 
Predictors of arterial inflammation by HIV status
 
In arteries from HIV- cases, intima inflammation was associated with hypertension (B = 0.52, P = 0.05) and ILAA (B = 1.54, P < 0.001) (Table 3). ILAA was also associated with adventitial inflammation (B = 1.13, P < 0.001) in this group. In arteries from HIV+ cases, older age (B = 0.05/year, P = <0.001) and ILAA (B = 0.89, P = <0.001) were associated with intima inflammation, whereas the use of cART at death (B = 0.72, P = 0.03) and a higher number of visits with CD4+ cell counts <100 (B = 0.06/visit, P = 0.03) were associated with adventitial inflammation.
 
In post hoc analysis in HIV+ cases, adventitial inflammation was associated with cART use at death in those with prior opportunistic infections (B = 0.60, P = 0.04), with higher viral loads at death in those with longer HIV infection duration (B = 0.003, P = 0.03) or higher viral loads at death in those with chronic severe immunosuppression (i.e. greater number of premortem visits with <100 CD4+ cell counts, B = 0.007, P = 0.04). There was no association between HIV-related variables with intima inflammation independent of atherosclerosis.
 
Discussion
 
Arterial inflammation in brain arteries was observed frequently among cases with and without HIV. In this sample, HIV+ cases had a higher inflammation score than HIV- cases, but this difference was mostly driven by a significant difference in adventitial inflammation in HIV+ cases. Intima inflammation was progressively more intense and widespread as the atherosclerotic phenotype evolved, but this effect was independent of HIV status. Inflammation in the media was typically observed in the context of intima inflammation. Among HIV- cases but not in HIV+ cases, intima inflammation was also the most important predictor of adventitial inflammation. Consequently, brain arteries in HIV+ cases appeared to have an enhanced susceptibility to develop adventitial inflammation compared with HIV- cases, independent of atherosclerosis or intimal inflammation.
 
The strong association noted between HIV and adventitial inflammation is of great interest. Contrary to what was seen in HIV- cases, adventitial inflammation in HIV+ cases was not entirely explained by associations with intimal inflammation because of atherosclerosis (Fig. 2). Adventitial inflammation is frequently reported in animal and human arterial specimens from HIV+ cases with 'HIV vasculopathy' [13,22,23]. HIV vasculopathy is characterized by a thin arterial wall, an atrophic media, and intimal fibrosis, but no atheromas, and thus is not typically considered to be atherosclerotic [24-26].
 
The source of inflammatory cells in the adventitia of those with HIV is not clear. Because the brain arteries are wrapped by the leptomeninges as they enter the skull, an association with aseptic meningitis and adventitial inflammation seems plausible. Aseptic meningitis is observed in about a fifth of patients with HIV in samples with a preponderance of immunosuppressed patients, and it is observed more frequently in brain specimens with evidence of parenchymal HIV brain disorder [4,27]. The association of adventitial inflammation as a predictor of dolichoectasia in arteries with a thin media further supports the notion that HIV vasculopathy is a form of pathological brain arterial remodeling observed predominantly in HIV cases with persistent immunosuppression, in which adventitial inflammation may be either a surrogate of immunosuppression per se or a marker of the underlying pathophysiology leading to thinning of the media and subsequent arterial dilatation. We considered latent VZV as a potential antigenic stimulus in the arterial wall given evidence that latent VZV is frequently found in cases with HIV, but adjusting for latent VZV did not change the association between HIV infection and inflammation [28,29]. Infection of the arterial wall by HIV is, in our view, a plausible hypothesis that fits well the pattern and associations reported between HIV and brain arterial remodeling; however, it is a hypothesis that remains to be tested.
 
Atherosclerosis has long been considered an inflammatory disease [30,31]. Macrophages are usually observed in coronary atherosclerosis and heavy inflammatory infiltrates in these plaques are considered a feature of vulnerability to rupture [32]. There is substantial evidence in HIV models of atherosclerosis (animal and human) that inflammation might also play an important role in the pathophysiology of vascular disease. For example, studies have demonstrated an increased expression of chemoattractant proteins in endothelial and other vascular cells (e.g., smooth muscle cells) upon exposure to HIV viral proteins like tat or p24 [11,22,33]. Not only is chemoattraction increased, but there is also a substantial increment in adhesive proteins in the endothelial surface, like vascular cell adhesion molecule-1 and endothelial-leukocyte adhesion molecule 1, that can facilitate the recruitment and transit of inflammatory cells into the arterial wall [34,35]. Given these data, it is not surprising that inflammatory cells (macrophages and/or lymphocytes) are frequently reported in the arterial wall of in-vitro and in-vivo specimens with HIV with atherosclerosis [22,33].
 
The results presented here confirm that intima inflammation rises and spreads out to the media as ILAA severity increases. The drivers of intima inflammation in atherosclerosis are beyond the scope of this discussion, but it is worth mentioning that among HIV+ cases, older age and ILAA were the most important determinants of intima inflammation. In a prior report including the specimens used for this study, we reported that the most important predictors of ILAA in HIV+ cases were diabetes, older age, low nadir CD4+ cell count, and higher CD4+ cell counts at death [36]. Contextualizing both studies, we conclude that ILAA is the most important predictor of intimal inflammation irrespective of HIV, and that among those with HIV; a higher CD4+ cell count may have enhanced the capability of the host to mount an inflammatory response against the arterial wall. This interpretation fits well with clinical evidence of increased aortic inflammation characterized by higher fludeoxyglucose uptake and increased soluble CD163+ (a marker of monocyte/macrophage activation) in those with HIV compared with control groups matched by traditional risk factors [12]. The arterial inflammatory process in HIV appears to be systemic, as evidenced by a significant increase in serum markers of endothelial activation in patients with HIV compared with uninfected controls, only partially blunted after initiation of cART [37]. Whether the antigenic stimulus for intimal inflammation differs by HIV status is still a matter of research, but understanding the mechanisms of ILAA is important, as ILAA accounts for up to 42% of strokes in HIV patients [7].
 
The results presented here need to be framed in the context of several limitations, including the biases referable to autopsy samples, the lack of a homogenous sample for HIV- cases with the inclusion of non-US cases, the inherent error and lack of precision attributable to immunohistochemistry, and the lack of other markers of inflammation that may have revealed a richer description of the complex immunological cascade likely present in these arterial specimens. Additionally, CD68+ antibody can cross-react with fibroblast and monocytes, but the reproduction of well known relationship between inflammation and atherosclerosis makes us believe that the cross-reaction with other cells is unlikely to reduce the significance of these findings [38]. Our study, however, has several strengths, including the relatively large sample size, the systematic processing of the specimens with reliable methods used to quantify and describe the arterial phenotypes and intensity of staining, the longitudinal data among HIV cases, as well as the comparable groups by age and sex.
 
We report here an association between HIV infection and inflammation in brain large arteries. Although intimal inflammation is closely linked to ILAA independent of HIV, adventitial inflammation was strongly associated with HIV and it was predictive of a thinner media and dolichoectasia. These results support a role for adventitia inflammation in the pathogenesis of HIV vasculopathy. Further understanding of the drivers of arterial inflammation may offer the opportunity to conceive novel therapies that may tackle the rising incidence of cerebrovascular disease in the HIV population.

 
 
 
 
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