Targeting the HIV-infected brain to improve ischemic stroke outcome

Abstract

HIV-associated cerebrovascular events remain highly prevalent even in the current era of antiretroviral therapy (ART). We hypothesize that low-level HIV replication and associated inflammation endure despite antiretroviral treatment and affect ischemic stroke severity and outcomes. Using the EcoHIV infection model and the middle cerebral artery occlusion as the ischemic stroke model in mice, we present in vivo analysis of the relationship between HIV and stroke outcome. EcoHIV infection increases infarct size and negatively impacts tissue and functional recovery. Ischemic stroke also results in an increase in EcoHIV presence in the affected regions, suggesting post-stroke reactivation that magnifies pro-inflammatory status. Importantly, ART with a high CNS penetration effectiveness (CPE) is more beneficial than low CPE treatment in limiting tissue injury and accelerating post-stroke recovery. These results provide potential insight for treatment of HIV-infected patients that are at risk of developing cerebrovascular disease, such as ischemic stroke.

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

“…ECV protein concentration was measured by BCA protein assay kit (Pierce). Equal amount of proteins (8)(9)(10)(11)(12)(13)(14)(15)(16) μg/lane) was loaded on sodium dodecyl sulfate polyacrylamide 4-20% ready gels (BioRad, Hercules, CA) and electrotransferred to a nitrocellulose membrane using a transfer pack system (BioRad). The blots were probed at 4°C with rabbit anti-ASC antibody (Catalog # AL177, Adipogen Life Sciences, San Diego, CA), rabbit anti-NLRP3 antibody (Catalog # LSB4321, LSBio, Seattle, WA) or mouse anticaspase-1 antibody (Catalog # sc-514, Santa Cruz Biotechnology Inc) (1:400) in 5% milk-TBS-T. After washing 3 times with TBS-T, the samples were incubated with secondary antibodies diluted at 1:20,000 (anti-mouse 800CW or anti-rabbit 680RD).…”

Cerebral Vascular Toxicity of Antiretroviral Therapy

“…In addition to aforementioned viral factors, elevated levels of ROS and increased circulating levels of proinflammatory molecules, such as TNF-α, IL-1β, and C-reactive protein, can contribute to underlying chronic inflammation in infected individuals (Brabers and Nottet 2006;Ross et al 2009;Younas et al 2016). These changes are accompanied by an increase in adhesion molecules on the brain endothelium, such as VCAM-1, ICAM-1, P-selecting, and platelet endothelial cell adhesion molecule (PECAM-1 or CD31) (Dhawan et al 1997;Wolf et al 2002;Bertrand et al 2019b). The accumulation of these inflammatory mediators can further lead to the development on vasculopathies associated with HIV infection (Chetty 2001).…”

“…Experimental studies also demonstrated that Efavirenz can have deleterious effects on ischemic stroke, leading to increased tissue damage and BBB deterioration (Bertrand et al 2016b). On the other hand, administration of low toxicity ART is beneficial for the outcome of stroke when compared to the untreated HIVinfected group (Bertrand et al 2019b). An additional factor to take into consideration is that co-morbidities can be exacerbated by ART toxicity.…”

“…What was once a fatal disease is now controlled, and the infected patients survive longer. In these long-term survivors, several pathologies are observed, such as cardiovascular, lipid, metabolic, and neurological disorders (Clifford and Ances 2013;Deeks et al 2013;Galescu et al 2013;Kebodeaux et al 2013;Lake and Currier 2013;Bertrand et al 2019b). Before the advent of ART, neurological disorders in HIV patients were often associated with severe cognitive dysfunction, such as HIV-associated-dementia.…”

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

“…Aβ deposition occurs mostly in the perivascular space [3,[7][8][9], which points to the brain microvessels having a role in amyloid pathology. In support of this notion, the blood-brain barrier (BBB), a critical player in the brain infection by HIV and the development of HIV-associated cerebrovascular comorbidities [10,11], was postulated to regulate Aβ homeostasis as an interface contributing to Aβ accumulation in the brain [12]. Indeed, it was demonstrated that the receptor for advanced glycation end products (RAGE) can mediate Aβ transport across the BBB and accumulation in the brain [13].…”