Clonal hematopoiesis in monocytes contributes to HIV-associated neuroinflammation

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Summary Extravasation of inflammatory monocytes across the blood-brain barrier (BBB) in response to human immunodeficiency virus type-1 (HIV) is a critical event that leads to chronic neuroinflammation, neurologic injury, and subsequent loss of cognitive abilities in a significantly large number of infected individuals. However, given the heterogeneity of monocytes that exists in HIV-infected individuals receiving anti-retroviral therapy (ART), it remains unknown as to whether the neuro-modulatory actions of monocytes are limited to select subset of monocytes. Directly relevant to the goals of RFA-21-250, our supporting data reveals that the ART-treated HIV- infected individuals harbor higher numbers of inflammatory monocytes (CD14lowCD16hi) in their circulation. These cells also exhibit characteristic features of clonal hematopoiesis (CH), such as loss of DNA methyltransferase 3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2) with concurrent increase in the expression of janus kinase-2 (Jak2 ; these three gene products, and few others, are often termed as CH drivers). Interestingly, subsequent experiments in various models suggested that this monocyte subset (1) translocate to the central nervous system (CNS) in response to ART, in platelet-dependent manner, (2) is neuro-modulatory in action, and (3) can be expanded following exposure of monocytes to activated platelets and ART. Based on these findings, we posit that the priming of monocytes by activated platelets potentiates ART-mediated clonal hematopoiesis in monocytes, leading to HIV-associated neurologic injury. In this model, we propose that the composite effect of activated platelets and ART results into clonal expansion of inflammatory (CD14lowCD16hi) monocyte subset with CH, and subsequent demethylation/induction of PSGL-1 gene in them. Functionally, these events facilitate the transmigration of such monocytes into the perivascular spaces within the CNS, where these cells differentiate into macrophage phenotype, while retaining CH profile, and contribute to the neuronal dysfunction. This model then, in full accordance with the available literature, accounts for how neurologic manifestations are initiated and maintained due to immune-CNS interaction in ART-treated HIV- infected individuals.