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.

Background. This study tests the hypothesis that increased elastolytic activity is associated differentially with dolichoectasia in individuals with and those without human immunodeficiency virus (HIV) infection.Methods. Large arteries from 84 autopsied brains from HIV-positive individuals and 78 autopsied brains from HIV-negative individuals were stained for metalloproteinase 2 (MMP-2), MMP-3, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, CD68, and caspase 3. Average pixel intensity was automatically obtained and categorized as high, moderate, or low. Dolichoectasia was defined as a lumen to wall ratio ≥95th percentile.Results. High MMP-9 staining alone (P = .001) or coexistent with low TIMP-2 staining was associated with dolichoectasia only in HIV-negative individuals (P = <.001). In HIV-positive individuals, MMP-9 was associated with dolichoectasia only when coexpressed with caspase 3 (P = .01). Thinning of the media was associated with CD68 staining (P = <.001) in HIV-negative individuals, while caspase 3 was associated with a thinner media only in HIV-positive individuals (P = .01). Media thickness modified the association between lumen to wall ratio and MMP expression.Conclusions. A role for MMP/TIMP balance in dolichoectasia appears more prominent in HIV-negative individuals, while apoptosis, mediated by caspase 3, is the most important determinant of media thinning in HIV-infected individuals. Furthermore, apoptosis and media thickness appear to mediate the effects of MMP in the HIV-infected population.

Background: The incidence of cerebrovascular events is rising in the HIV population but little is known about the mechanisms of vascular injury among patients with HIV population. Methods: Large cerebral arteries were obtained from autopsies in 80 HIV+ cases and 80 HIV- controls, matched for sex and age ± 3 years, range 30-84. Arterial size, atherosclerosis phenotype, luminal stenosis, and media thickness were obtained in each artery. The average pixel intensities (AI) of metalloproteinase (MMP)-2, MMP-3, MMP-9, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 was assessed with immunohistochemistry defining high intensity as an AI in the upper tertile. Inflammation was assessed with CD68 staining. All estimates were adjusted for age, sex, ethnicity, vascular risk factors and cocaine use. Results: Arterial inflammation was associated with greater staining intensity of MMP3 (Beta=0.36, P=0.003) and TIMP2 (Beta=0.29, P=0.002) in HIV+ cases, but not in HIV- controls. The association of HIV with MMP3 was independent of whether the inflammation was located in the media, intima, or adventitia, while for TIMP-2 the association was only significant with intima inflammation (Beta=-0.36, P=0.03). Cerebral arteries in HIV + cases with high intensity of MMP3 staining had thinner media (Beta=-2.3, P= 50 viral copies/mL (B=0.62, P=0.04), Nucleoside Reverse Transcriptase Inhibitor (B=1.08, P=0.009) or protease inhibitor use at the time of death (B=-0.64, P=0.05), vascular risk factors (B=0.51, P=<0.001), and diabetes (B=1.2, P=<0.001), were associated with higher expression of MMP3. There were no significant associations between inflammation and MMP2, MMP9 and TIMP1 intensity staining. Conclusions: Arterial inflammation in HIV+ cases is associated with greater expression of MMP3, and arteries with higher expression of MMP3 have a thinner media, despite thicker walls, and greater degrees of luminal narrowing. Through thinning of the media, MMP3 may play a role in HIV-associated dolichoectasia; through secondary effects, it may contribute to paradoxical luminal stenosis.