Accelerated cognitive aging in chronically infected HIV-1 positive individuals despite effective long-term antiretroviral therapy.

People living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9 years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons.