Sex-specific gut mycobiome dysbiosis activates macrophage dectin-1 signaling to drive neurobehavioral deficits in EcoHIV-infected mice

• EcoHIV induces a female-specific expansion of gut Malassezia globosa. • Malassezia abundance links to social and cognitive deficits in EcoHIV mice. • EcoHIV elevates colonic dectin-1 + macrophages driving immune dysregulation. • β-glucan pachyman reverses EcoHIV-induced social and memory impairments. • Pachyman normalizes EcoHIV-associated immune–metabolic disturbances. • ART-treated PWH exhibit elevated circulating dectin-1 + monocytes. HIV-associated neuropsychiatric and neurocognitive disorders remain prevalent in people living with HIV (PWH) despite antiretroviral therapy (ART), underscoring the need for novel mechanistic insights and therapeutic strategies. Emerging evidence suggests that gut fungal dysbiosis contributes to neuroimmune dysfunction. Nevertheless, its contribution to HIV-associated psychosocial and cognitive deficits is poorly understood. Here, using the murine EcoHIV infection model that recapitulates key features of HIV neuropathogenesis, we identify a female-specific gut fungal signature associated with EcoHIV-induced psychosocial and cognitive impairments. Although EcoHIV infection induces behavioral impairments in both male and female mice, the present study identifies a distinct, female-associated mechanism involving gut Malassezia globosa enrichment and activation of a dectin-1 + intestinal macrophage axis. Treatment with pachyman, a fungal 1,3-β-D-glucan derived from Poria cocos and an established dectin-1 ligand, reversed these deficits without affecting locomotor or anxiety-related behaviors. Mechanistically, EcoHIV infection increased the frequency of colonic dectin-1 + macrophages, which correlated with both social avoidance and Malassezia globosa abundance, and pachyman treatment reversed this increase. EcoHIV infection also disrupted immune-related metabolic pathways in the gut, which were restored by pachyman treatment. We further observed a parallel increase in dectin-1 + circulating monocytes in ART-treated PWH, supporting a conserved dectin-1–driven innate immune signature across mouse and human studies. These findings identify a female-associated gut Malassezia globosa –dectin-1 + macrophage axis linked to HIV-associated psychosocial and cognitive deficits, and suggest pachyman as a potential candidate for integrative therapeutic strategies.