Targeting the HIV-infected brain to improve ischemic stroke outcome
Luc Bertrand (firstname.lastname@example.org) and Michal Toborek (email@example.com) University of Miami Miller School of Medicine, Department of Biochemistry and Molecular Biology, Miami, FL
The field of HIV research has changed immensely in the last three decades. Leaps and bounds have been made to elucidate the mechanisms of replication used by the virus, how it circumvents host resistance mechanisms, and fortunately, how several antiretroviral drugs have been found. Their discovery drastically changed the disease profile and enabled infected patients to live with a near normal life expectancy. However, as this population aged, it was discovered that HIV-infected patients were more susceptible to the development of several co-morbidities1. Higher incidence of metabolic, cardiovascular, and neurodegenerative diseases was observed, and a new fight emerged; discovering how the prolonged survival of these patients leads to increased susceptibility to co-morbidities. Initial observations indicated that following the implementation of highly active antiretroviral therapy (ART), the virus was inactive. However, as tools became more sensitive, it became apparent that low-levels of HIV replication persisted, especially in the brain, where entry of antiretroviral therapeutics is limited. In addition, while ART provided incalculable benefits, the therapy was not without its own pitfalls as ART-related toxicity can develop. Our research group focuses on the interaction between HIV infection and antiretroviral treatments in the context of the blood-brain barrier (BBB). This area is of high interest given that more than a third of patients living with HIV will develop neurological complications. Past discoveries demonstrated that the BBB is highly affected by both infection and also by ART, which can lead to vascular and CNS toxicity.
Given the prevalence of cerebrovascular disease in infected patients, we used our expertise in research on ischemic stroke and on a mouse model of HIV infection to investigate how HIV can affect ischemic stroke progress and impede recovery2. We first demonstrated that ischemic infarct injury was amplified by HIV, and that recovery was delayed. This correlates with an increase in proinflammatory molecules at the BBB and its weakening by the infection prior to induction of ischemia. This predisposes the brain to injury and also increases pro-inflammatory responses after the cerebrovascular event. In addition, we detected that HIV-1 levels increase after ischemic stroke both in the CNS and thereafter in the circulation. This points to an important finding that an ischemic event can result in reactivation of latently infected cells in the CNS and stimulate an escape of the virus to the periphery. This finding is highly relevant to approaches to cure HIV, which needs to determine competent HIV reservoirs that have to be eliminated. To determine if the CNS reservoirs are important to the observed increase in ischemic stroke injury, we compared two drug regimens that differ in their ability to reach the CNS. In doing so, we were able to demonstrate that a therapy that better treats HIV in the CNS results in much improved disease outcome, and also reduces post-stroke HIV reactivation below detectable levels. The findings uncovered during this research demonstrate the intricate relationship between HIV, ART, and comorbidities; further highlighting the need for extensive research in this domain to improve the lives of people living with HIV, and ultimately, to cure HIV infection.
1. Winston A, Underwood J. Emerging concepts on the use of antiretroviral therapy in older adults living with HIV infection. Curr Opin Infect Dis 28, 17-22 (2015).
2. Bertrand L, Méroth F, Tournebize M, Leda AR, Sun E, Toborek M. Targeting the HIV-infected brain to improve ischemic stroke outcome. Nat Commun 10, 2009 (2019).