HIV Transgenic Mouse Monocytes Display Increased In Vivo Migration Across the Blood Brain Barrier Associated with Increased Expression of Genes Associated with Mononuclear Leukocyte Migration

Soon after HIV acquisition, circulating HIV-infected monocytes cross the blood-brain barrier (BBB) and infect resident brain microglia and other susceptible cells, establishing a potential viral reservoir. Despite supressive antiretroviral therapy, these HIV-infected cells mediate a neuroinflammatory process causing HIV-associated neurocognitive deficites (HAND) in at least 20% of people with HIV. Continued migration of HIV-infected monocytes into the brain may further exacerbate neuroinflammation and replenish viral reservoirs. To ascertain how HIV infection facilitates monocyte passage across the BBB in vivo, we developed a novel mouse model to quantify circulating monocytes supporting HIV production that migrated into the brain. We demontrate that significantly more monocytes from HIV-transgenic mice, capable of supporting HIV production, crossed the BBB compared to control transgenic mouse monocytes. This difference was particularly pronounced after recipient mice were treated with lipopolysaccharide (LPS). To explore the underlying mechanism, we compared the transcriptomes of HIV transgenic mouse monocytes and control mouse monocytes and identified multiple differentially expressed genes linked to mononuclear leukocyte trafficking, including several associated with monocyte chemotaxis. We also evaluated the effect of substance use in combination with HIV infection on monocyte migration across the BBB into the brain by treating HIV transgenic mice with either morphine or methamphetamine. Short-term exposure to either drug did not significantly alter the migration of HIV-transgenic monocytes across the BBB.