The role of co-infections and the microbiome in the brain and mental health of people living with HIV

People with HIV (PWH) face increased risk of cognitive impairment and mental health disorders. While HIV itself plays a key role, growing evidence highlights the importance of additional contributors, including co-infections and microbiomes, especially in the context of long-term antiretroviral therapy. This perspective integrates findings from clinical virology, microbiology, neurology, and immunology to examine how co-infections, such as Herpesviruses, Toxoplasma gondii, and Mycobacterium tuberculosis, as well as human biomes, affect the central nervous system (CNS) of PWH. We provide examples of diverse mechanisms, including disruption of T-cell receptor repertoires, chronic neuroinflammation, modulation of the CNS HIV reservoir, impaired blood–brain barrier integrity and glymphatic clearance, epigenetic changes, and communication between microbial communities and the CNS. We identify converging and distinct mechanistic patterns across pathogens that may contribute to neurological outcomes long considered exclusive to HIV. We propose a new framework for hypothesis generation and research design centered on the concept of “microbial neuro-burden.” Neuro-HIV research should account for the cumulative and interactive effects of HIV, co-infections, and microbial dysbiosis within (and outside) the CNS or risk overlooking key contributors and missing opportunities for effective prevention and intervention to preserve brain health in PWH.