Osteopontin knockdown reverses HIV-induced cognitive deficits and influences motivation-related behavior.

The neurological complications of HIV or NeuroHIV, representing a spectrum of disorders in people living with HIV, are characterized by memory impairments and cognitive decline. Osteopontin/secreted phosphoprotein 1 (OPN/SPP1), a multifunctional cytokine-like protein secreted by multiple cell types in and outside the central nervous system (CNS), is highly elevated in NeuroHIV and other well-known neurodegenerative disorders. Additionally, previous neuroimaging studies have demonstrated a role for OPN in regulating neuroinflammatory signaling. However, the potential links between CNS-specific functions of OPN and behavior remain unclear. In this study, we used NSG immunodeficient mice (hu-mice) engrafted as neonates with HIV-susceptible human CD34 + hematopoietic stem cells (HSCs) to test the hypotheses that chronic viral infection impairs cognitive function and that systemic disruption of OPN expression can ameliorate the resulting behavioral deficits. We found that HIV-infected hu-mice treated with inhibitory OPN-aptamers to knock down OPN exhibited altered exploratory and anxiety-related behavior compared to uninfected animals. A synergistic relationship between HIV and OPN impaired cognitive performance in an object recognition memory task that was not observed in uninfected mice. The knockdown of OPN expression alleviated this recognition deficit. Interestingly, only the HIV-infected OPN knockdown group showed a marked reduction in motivation/self-care related behavior. Additionally, we found reduced OPN expression in cells located in the midbrain ventral tegmental area of HIV-infected mice, demonstrating for the first time, the systemic delivery of functional aptamers to the brain. Notably, there were no significant differences in OPN levels in similarly treated uninfected mice. Notably, a decrease in tyrosine hydroxylase (TH) expression in midbrain dopaminergic neurons of OPN knockdown compared to OPN wildtype mice, irrespective of HIV infection status was foundsuggests a potential gene expression regulatory link between OPN and TH. These findings highlight the multifaceted role of OPN in HIV-associated neurobehavioral dysfunction, suggesting context-dependent contributions to both cognitive and apathy-based processes.