An interplay between HIV infection and cerebrovascular toxicity of methamphetamine
Minseon Park 1 , Andrzej Małecki 2 , and Michal Toborek 1,2,
1 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
2 Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice 40-065, Poland
Corresponding Author: Michal Toborek;
A substance use disorder (SUD) is a well-recognized risk factor for HIV-1 infection; however, little is known about molecular interactions between psychoactive substances and HIV-1 in the brain, and how they impact their long-term effects. The problem is important because SUD, including methamphetamine (METH) use, raises the risk of contracting or transmitting HIV-1 not only for individuals who inject the drug, but also for noninjecting users, as it is associated with an increase in risky sexual behavior. Moreover, METH use, either alone or in combination with other drugs, is associated with failure of viral suppression. People living with HIV-1 (PLWH) who engage in METH use display exacerbations in key pathophysiologic processes that are linked to faster clinical HIV-1 progression. Indeed, the combination of HIV-1 infection and METH dependence causes more profound neurocognitive deficits and structural brain abnormalities than either condition alone. METH use increases genomic activities to become transcriptional events related to neurodegeneration, dopaminergic deficits and decreased cognitive and executive functions. Our research has focused on the central hypothesis that the immunomodulatory impact of METH on BBB pericytes drives their HIV-1 infection and alters their interactions with neural progenitor cells (NPCs), which are located in perivascular niches in a close proximity to the BBB. We identified that both BBB pericytes and NPCs can be infected with HIV and characterized the signaling pathways by which exposure to METH and HIV contributes to aberrant neurogenesis, migration, and proliferation of NPCs. Overall, this research contributes to a better understanding of the influence of psychoactive substances on pericyte HIV-1 reservoirs in the CNS in order to design future therapies for reservoir clearance and a cure for HIV-1, especially for individuals living with HIV-1 who experience a SUD.
Funding: Supported by the National Institutes of Health (NIH) grants DA044579 and DA050528, and by the National Science Centre (NSC) grant 2019/35/B/NZ7/03155.