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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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE319558 | GEO | 2026/03/13

REPOSITORIES: GEO

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Project description:Persistent and elevated systemic inflammation contributes to the increased risk of cardiovascular and metabolic diseases in persons with HIV (PWH). , but aspects of the innate and adaptive immune response to HIV and other chronic co-infections that promote the development of these comorbid conditions remain unclear. We used mass cytometry and the tracking responders expanding (T-REX) workflow to define differences in circulating cells of the innate and adaptive immune arms, which differentiate non-diabetic and prediabetic/diabetic persons with HIV (PWH) on long-term antiretroviral therapy (ART). We found a significantly higher proportion of circulating CD14+ monocytes complexed with T cells, B cells, and NK cells among PWH with diabetes. The CD3+ T cells in these complexes were predominantly CD8+ memory T cells. The CD3+ CD14+ T cell-monocyte complexes are pro-inflammatory and negatively associated with plasma interleukin-10 levels and circulating CD4+ T regulatory cells. Using transmission electron microscopy, we observed heterogeneous interactions between CD3+ T cells and monocytes within the complexes, including formation of immune synapses and phagocytosis. 10x Chromium single-cell sequencing RNA transcriptomic analysis of CD3+ CD14+ doublets showed differential expression of genes involved in T cell activation and the adaptive immune response compared to monocytes that were not complexed with other immune cells. Notably, there were significantly more copies of HIV RNA per cell in the CD3+ CD14+ T cell-monocyte complexes compared to CD14+ monocytes or CD3+ CD4+ T cells alone, and HIV virions were observed in both T cells and monocytes within the doublets?. Metabolically, CD3+ CD14+ T cell-monocyte complexes had high glucose-dependence with minimal mitochondrial dependence. Taken together, CD3+ CD14+ T cell-monocyte pairs are functional and physically interacting immune cell complexes which might be enriched with HIV. These complexesare increased among individuals with diabetes and may be a target for future HIV cure studies and diseases of aging.

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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

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