Metalloproteinases and Brain Arterial Remodeling Among Individuals With and Those Without HIV Infection

Gutierrez, José; Menshawy, Khaled; Goldman, James E.; Dwork, Andrew J.; Elkind, Mitchell S.V.; Marshall, Randolph S.; Morgello, Susan

doi:10.1093/infdis/jiw385

Cited by 16 publications

(10 citation statements)

References 23 publications

(26 reference statements)

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“…From this result, we conclude that a sufficient CD3 ϩ T cell count may be necessary to generate inflammatory responses in HIV that may lead to luminal reduction and possibly blood flow reduction. Hypertrophic outward remodeling as a response to intimal lymphocytic inflammation may relate to increased elastolytic and medium apoptosis, a phenomenon that we have previously described in the same cohort in association with adventitial macrophages (11) and that others have documented in aortic or coronary aneurysmal dilatation (12)(13)(14). It is possible that immunosuppression interacts with intimal CD3 ϩ T cells in a way that potentiates dilatation rather than constriction, as among those with a CD4 count of Ͼ200; it is also possible that dilatory effects are predicated on other cell populations.…”

Section: Discussionsupporting

confidence: 66%

Brain Large Artery Lymphocytic Inflammation and Human Immunodeficiency Virus-Related Brain Arterial Remodeling

Shenoy

Dwork

Elkind

et al. 2018

J Virol

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The pathogenesis of increased stroke risk in Human Immunodeficiency Virus (HIV) remains unclear. Our study investigated the relationship between adventitial and intimal CD3+ T cells and brain arterial remodeling that potentially contributes to HIV-related vasculopathy and stroke. Large brain arteries from 84 HIV+ cases and 78 HIV- cases were analyzed to determine interadventitial and luminal diameters, intimal and wall thickness, percentage stenosis, and presence of atherosclerosis. Immunohistochemical analysis was performed to detect and visually score CD3, a pan T cell marker, in the intima and adventitia. Our study showed that adventitial CD3+ T cells are lower among persons with HIV, especially if CD4<200, though intimal CD3+ T cells did not differ by HIV status. Among those with HIV but CD4<200 at time of death, intimal CD3+ T cells were associated with hypertrophic outward remodeling, while among those with HIV and CD4>200 or HIV- controls, intimal CD3+ T cells were associated with hypertrophic inward remodeling. We conclude that intimal lymphocytic inflammation is involved in brain arterial remodeling that may contribute to HIV-related cerebrovascular pathology. Although mortality from Human Immunodeficiency Virus (HIV) has decreased with the use of combination antiretroviral therapies, there is now an increased risk of cardiovascular and cerebrovascular disease associated with HIV. Thus, there is a need to understand the pathogenesis of stroke in HIV infection. Our study examines how lymphocytic inflammation in brain arteries may contribute to increased cerebral vasculopathy. With this understanding, our study can potentially help direct future therapies to target and prevent brain arterial remodeling processes associated with HIV.

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Section: Discussionsupporting

confidence: 66%

Brain Large Artery Lymphocytic Inflammation and Human Immunodeficiency Virus-Related Brain Arterial Remodeling

Shenoy

Dwork

Elkind

et al. 2018

J Virol

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“…Furthermore, tetracycline therapy may decrease the risk for hemorrhage in patients with brain vascular malformations such as arteriovenous malformation and intracranial aneurysm (26). Interestingly, a recent study that investigated MMPs and brain arterial remodeling confirmed that high MMP-9 expression, alone or combined with low TIMP-2 expression, was associated with dolichoectasia in HIV-negative individuals; high expression of MMP-9, accompanied by expression of caspase 3, was associated with dolichoectasia in HIV-positive individuals (10). MMP-2 levels were found to be associated with cervical/intracranial carotid artery dolichoarteriopathies (11).…”

Section: Discussionmentioning

confidence: 99%

MMP-9, Vertebrobasilar Ectasia and Vertebral Artery Dominance in Vertigo or Dizziness Patients With Vascular Risk Factors

et al. 2020

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Background and Purpose: Although vertebrobasilar ectasia (VBE) is diagnosed with increasing frequency, it is not clear whether this is because of altered hemodynamics caused by the effects of matrix metalloproteinases (MMPs) and/or vertebral artery dominance (VAD). Therefore, we investigate the relationship between plasma levels of MMPs and VBE in patients with vertigo or dizziness who also have vascular risk factors, in order to determine whether high levels of MMPs in VBE are independent of VAD. Methods: We prospectively studied 285 patients with vertigo or dizziness and at least one vascular risk factor. Plasma levels of MMPs, tissue inhibitor of metalloproteinases (TIMPs) and cathepsin L were measured. Subjects were classified as VBE-negative or VBE-positive, who were further classified based on the presence of VAD with magnetic resonance angiography. Acute ischemic stroke was screened by diffusion-weighted imaging, generally after bedside evaluation and the drawing of blood samples. Receiver operating characteristic (ROC) curves were applied to evaluate the utility of these potential biomarkers in predicting risk for ischemic stroke. Results: The prevalence of VBE in patients with vertigo or dizziness was 16.5%. Of the 82 patients with ischemic stroke, 14 strokes involved the cortex or subcortex. MMP-9 levels were significantly higher in the VBE-positive group than in the VBE-negative group (P = 0.022). There was a significant difference in the risk of posterior circulation ischemic stroke between the VBE-positive group and the VBE-negative group (P = 0.002). Levels of MMP-2 and cathepsin L tended to be higher in the VBE-negative group (P = 0.054, P = 0.060, respectively). Compared with the non-VAD subgroup, levels of MMP-2,−3,−9, TIMP-1,−2, and cathepsin L were similar in the VAD subgroup. ROC analysis showed that MMP-9 predicted risk for ischemic stroke (AUC = 0.582, 95%CI, 0.510-0.654, P = 0.030). Zhang et al. MMP-9 Is Associated With Vertebrobasilar Ectasia Conclusions: MMP-9 was associated with VBE and independent of VAD. High levels of MMP-9 may predict risk for ischemic stroke in patients with vertigo or dizziness who also have vascular risk factors.

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“…[42] A thinner media layer might be a preclinical stage in HIV vasculopathy development. [43] A study in China found that cerebrovascular endothelial dysfunction associated with HIV seropositivity may be important in the pathogenesis of cerebrovascular dysfunction. [44] CD8 + encephalitis, an emerging clinical entity pathologically associated with marked perivascular infiltrates with polyclonal CD8 + lymphocytes, may be a newly recognized HIV vasculopathy though further studies are needed to fully delineate the pathophysiological processes underlying this condition.…”

Section: Hiv-associated Cerebrovascular Disordersmentioning

confidence: 99%

Global HIV neurology

Thakur

Boubour

Saylor

et al. 2019

Aids

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: Neurological conditions associated with HIV remain major contributors to morbidity and mortality and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence shows that the CNS may serve as a reservoir for viral replication, which has major implications for HIV eradication strategies. Though there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of neurological conditions associated with HIV infection, significant scientific gaps remain. In many resource-limited settings, ARVs considered second or third line in the United States, which carry substantial neurotoxicity, remain mainstays of treatment, and patients continue to present with severe immunosuppression and central nervous system (CNS) opportunistic infections. Despite this, increased global access to cART has coincided with an aging HIV+ population with cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. Further neurological research in low-income and middle-income countries (LMICs) is needed to address the burden of neurological complications in HIV+ patients, particularly regarding CNS viral reservoirs and their effects on eradication.

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Metalloproteinases and Brain Arterial Remodeling Among Individuals With and Those Without HIV Infection

Cited by 16 publications

References 23 publications

Brain Large Artery Lymphocytic Inflammation and Human Immunodeficiency Virus-Related Brain Arterial Remodeling

Brain Large Artery Lymphocytic Inflammation and Human Immunodeficiency Virus-Related Brain Arterial Remodeling

MMP-9, Vertebrobasilar Ectasia and Vertebral Artery Dominance in Vertigo or Dizziness Patients With Vascular Risk Factors

Global HIV neurology

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