Brain large artery inflammation associated with HIV and large artery remodeling

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.

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

“…Of interest, the intense costaining of TNF-α and MMP-9 was associated with dolichoectasia. Moreover, the monocyte chemotactic protein 1 staining intensity was associated with HIV infection and with adventitial macrophages, which we have demonstrated are far more prevalent among cases with HIV infection [13]. This association may lend support to the role that inflammation and reactive oxygen species have in the activation of the zymogen forms metalloproteinases and inflammatory cell recruitment to the arterial wall [23].…”

“…We validated the score against cross-sectional areas derived by automated pixel segmentation of brown staining. This method has good reliability [13].…”

“…Each microphotograph was processed to remove debris, blood residues, and folding artifacts, as described previously [13]. Average pixel intensity for MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TNF-α, and caspase 3 were obtained automatically, using the Visiopharm Integrator System, version 4.6.3.857 (Hoersholm, Denmark), by color thresholding.…”

Motor function declines over time in human immunodeficiency virus and is associated with cerebrovascular disease, while HIV-associated neurocognitive disorder remains stable

“…The etiology of cerebrovascular disease in HIV is likely related to a combination of traditional vascular risk factors and HIV-specific factors. HIV infection has been associated with greater adventitial inflammation of large brain arteries and dolichoectasia, compared to HIV-negative controls (Gutierrez et al 2016), and in a recent review (Benjamin et al 2016), several types of HIV-associated vas-culopathies were defined. Given this, it is possible that an increasing burden of cerebrovascular disease in the aging HIV population is one explanation why motor abnormalities still accompany cognitive dysfunction, even when the most severe form (i.e., HAD) is in decline.…”

Human immunodeficiency virus and cerebrovascular diseases – review

“…While the strength of the asso ciations and the pathogenic mechanisms remains a matter of debate, autopsy studies evaluating the cerebral vasculature in HIVinfected patients demonstrate a variety of patholog ic changes. Small vessels appear to develop a vasculopathy, with perivascular space dilation, infarction, pigment depo sition, vessel wall mineralisation, and perivascular cell in filtrates, all without evidence of a vasculitis [6], but recent studies have implicated inflammation as a course of vascular disease in the central nervous system (CNS) [9,10]. In larg er cerebral vessels, progressive vessel dilation occurs in HIV infection, potentially mediated by a thinner media layer leading to aneurysm formation [11].…”