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 suppressive antiretroviral therapy, these HIV-infected cells mediate a neuroinflammatory process causing HIV-associated neurocognitive deficits (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 demonstrate 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.IMPORTANCEOver 20% of people with HIV (PWH) develop cognitive and neurological deficits despite antiretroviral therapy. While the blood-brain barrier (BBB) normally prevents brain entry of circulating monocytes, HIV enables infected monocytes to traverse the BBB, establish viral production within the brain, and subsequently infect microglia and other cells, which drives neuroinflammation, neuronal injury, and neurocognitive impairment. To investigate how HIV stimulates in vivo migration of circulating monocytes across the BBB, we developed a novel mouse model utilizing HIV-transgenic mouse monocytes that support HIV production. After intravenous injection, a significantly higher number of HIV-transgenic monocytes migrated into the brains of wild-type mice compared to control transgenic monocytes, particularly after lipopolysaccharide (LPS) treatment. We identified multiple genes differentially expressed in HIV-transgenic monocytes associated with mononuclear leukocyte trafficking linked to HIV-mediated induction of monocyte transmigration across the BBB. These genes may represent therapeutic targets to prevent HIV-infected monocyte migration into the brain.
Sydenstricker et al. (Mon,) studied this question.