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Introduction: By virtue of their infection, HIV+ patients are subject to chronic inflammation, and show an increased risk for stroke when compared to uninfected controls. We hypothesized that HIV infection would be associated with increased atherosclerotic plaque vulnerability.Methods: Large brain arteries from 162 autopsied individuals (84 with HIV) were stained for metalloproteinase (MMP)-2, MMP-3, MMP-9, Caspase-3, and tumor necrosis factor (TNF)-α, factors reported to increase plaque vulnerability. We measured intensity of staining for each protein in the fibrous cap and scored each as 0 (most intense staining not in cap) or 1 (most intense staining in cap). We then added the ratings from the five stains and created a vulnerability score ranging from 0-5. CD3+ cells (lymphocytes) and CD68+ cells (macrophages) were also rated using semi-quantitative scores. Rating was blind to HIV status. We constructed multilevel models to obtain the β estimates and their 95% confidence intervals (β, 95%CI), adjusting for demographic characteristics, vascular risk factors, and HIV-related immune variables.Results: For the entire sample, the plaque vulnerability score was associated with higher degree of luminal stenosis (0.04, 0.02-0.06) and larger arterial size (0.5 per mm, 0.2-0.8), but not with HIV (-0.65, -2.24-0.95). However, in a subset of individuals with atherosclerosis (n=21), there was a statistical interaction (P<0.04) between HIV and vulnerability score. In a stratified model in HIV+ cases only, a CD4 count of > 200 cells/ul at death was associated with higher vulnerability score (1.42, 0.08-2.76) compared with subjects who remained immunosuppressed. Predictors of vulnerability score among HIV+ subjects included higher CD3 score (1.12, 0.15-2.09), older age (0.18 per year, 0.12-0.25), diabetes (3.00, 1.69-4.24), lower CD4 nadir (-0.01, -0.02to -0.007), antiretroviral use at death (-2.08, -3.84 to -0.32).Conclusions: Plaque vulnerability is positively associated with a higher blood CD4 count, lower CD4 nadir and higher lymphocytic inflammation in brain arteries among HIV+ cases. Investigating the role of HIV-related chronic inflammation and plaque vulnerability may help us better understand the higher risk of stroke among those with HIV.