Targeting HIV-infected brain to improve stroke outcome

In the era of highly active antiretroviral therapy, the HIV prognostic has changed from a deadly to a chronic disease. While the virus is repressed, several co-morbidities, including cardiovascular disease are still present in long term survivors. HIV positive individuals are more at risk of having strokes and also suffer from a less favorable recovery prognostic. Our hypothesis is that despite efficient HAART, residual HIV presence can contribute to stroke severity. In addition, we also hypothesize that viral reservoirs in the brain contribute to injury and that efficient treatment using high CNS penetration effectiveness (CPE) drugs could benefit disease outcome. Previous publications in our laboratory, based on the EcoHIV mouse model, demonstrated that infection affects the integrity of the functions of the blood-brain barrier. In the current study, we observed that infection by EcoHIV resulted in a significant increase in infract size both at early and late post-stroke when compared to mock infected animals. In addition, a recovery from stroke injury was seen in control animals, this reduction was not visible in EcoHIV infected mice. Upon further examination, we were able to demonstrate that the induction of stroke resulted in an increase in HIV presence in the affected hemisphere, with infected cells situated primarily near or at the border of the infract area. The majority of cells harboring the virus were from the macrophage/microglial lineage. We next employed several immune markers to examine if the immune reaction to the tissue injury and the more prominent viral presence could be responsible for the delay in infract recovery. We observed a trend for an increase in inflammatory markers in EcoHIV infected mice, especially those associated with the monocyte/macrophage/neutrophil response. We are currently investigating the potential therapeutic efficacy of targeting the HIV CNS reservoir using a high CNS penetrating efficacy therapy. The successful implementation of this regiment would be highly beneficial in HIV patients at risk of cerebrovascular disease.