HIV-1 soluble gp120 in cerebrospinal fluid is associated with poorer motor domain neurocognitive performance in virally suppressed people with HIV

Background: – Despite effective antiretroviral therapy (ART), neurocognitive impairment (NCI) persists in 30–50% of virally suppressed people with HIV (VS PWH). The mechanisms underlying this persisting NCI remain incompletely understood. Soluble gp120 (sgp120) has been detected in the plasma of PWH on ART and may contribute to inflammation and CD4+ T-cell depletion in the presence of non-neutralizing anti-cluster A antibodies (Abs). gp120 can induce neurotoxicity, leading to neuronal damage both in vitro and in transgenic mice. Objective: – To determine whether sgp120 and anti-cluster A Abs are detectable in the cerebrospinal fluid (CSF) of VS PWH and to evaluate whether their presence is associated with domain-specific neurocognitive performance. Methods: – We analyzed paired plasma and CSF samples from 146 VS PWH and 37 unsuppressed PWH. Neurocognitive performance was assessed using a comprehensive neuropsychological testing battery across multiple domains, from which demographically adjusted T-scores for each test were derived. Levels of sgp120 and anti-cluster A Abs were measured to evaluate their association with neurocognitive performance in PWH. Results: – Sgp120 and anti-cluster A Abs were detected in the CSF of 11 and 26% of VS PWH, respectively. Detection of CSF sgp120 was associated with lower neurocognitive motor-domain T-scores (Mann–Whitney U, P = 0.039; Cliff's δ = −0.33). This association was confined to sgp120 in the CSF and was not observed for sgp120 in plasma or for anti-HIV antibodies in the CSF. Conclusion: – These findings suggest that central nervous system (CNS) exposure to sgp120 may contribute to poorer motor neurocognitive performance in VS PWH. Strategies targeting CSF sgp120-related biomarkers warrant further investigation as potential approaches to mitigate NCI in VS PWH.