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; This email address is being protected from spambots. You need JavaScript enabled to view it.  

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.