Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system, collectively known as neuro-PASC. Notably, people living with HIV (PWH) many of whom suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction collectively known as neuroHIV are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuroHIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes and pericytes Our results demonstrated that first, both all brain cells support restrictive SARS-CoV-2 replication in presence or absence of HIV infection. Furthermore, in both mono and co-infected cells, there was a notable increase in the expression of SARS-CoV-2 host cell entry factors like ACE2, TMPRSS2, NRP1, and TRIM28 and inflammatory mediators. Moreover, conditioned media collected from astrocytes and pericytes were neurotoxic. Additionally, proteomic analysis has revealed distinct pathway regulation across infection conditions, with gene set enrichment highlighting top pathways linked to neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis. These findings underscore the potential chances of exacerbate neurological complications in PWH after SARS-CoV-2 infection.