Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

Abstract

Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

Dopamine, Immunity, and Disease

“…All five dopamine receptor subtypes have been identified on human microglia ( McKenna et al, 2002 ; Mastroeni et al, 2009 ), human microglial cell lines ( Matt et al, 2021 ) and rodent microglial cells (Farber et al, 2005; Kettenmann et al, 2011 ; Huck et al, 2015 ; Kopec et al, 2018 ) although not every study detected all subtypes. There may be an age-associated effect, as cultured human microglia from elderly individuals did not express Drd5 mRNA despite the presence of mRNA for the remaining dopamine receptors ( Mastroeni et al, 2009 ).…”

“…Further studies show that D1-like transcript levels correlate with CCR5 transcript levels, and that dopamine exposure significantly increases the amount of CCR5 on the surface of hMDMs and in the human C06 microglial cell line. Further, dopamine increased HIV replication in both human microglial cell lines and induced pluripotent stem cell–derived human microglia ( Matt et al, 2021 ). Together, these data indicate that dopamine increases viral replication by activating a noncanonical signaling pathway mediated by both types of dopamine receptors to induce changes in CCR5 that increase HIV entry into myeloid cells.…”

“…Cocaine also upregulated CCR5 gene expression in the NAc and VTA in uninfected rats ( Nayak et al, 2020 ). Defining the interaction between dopamine with this coreceptor is particularly important because dopamine could interfere with the effectiveness of antiretroviral drugs like maraviroc, which target CCR5 ( Matt et al, 2021 ).…”

Co-receptor signaling in the pathogenesis of neuroHIV

“…Stimulants include methamphetamine (Meth), cocaine, and prescription drugs used to treat conditions such as ADHD, all of which act by directly increasing CNS dopamine [ 508 – 510 ]. Dopamine, and by extension substance abuse, has been shown to modulate HIV infection, replication and inflammation, as well as alter the efficacy of the CCR5 entry inhibitor Maraviroc [ 66 , 373 , 465 , 509 , 511 – 513 ], although a comprehensive discussion of the role of dopamine in HIV neuropathogenesis is beyond the scope of this review. However, studies also show that stimulants can directly synergize with gp120 to exacerbate neuropathology [ 387 , 408 , 437 , 514 – 520 ].…”

Psychostimulant-induced aberrant DNA methylation in an in vitro model of human peripheral blood mononuclear cells

“…However, PBMCs express proteins related to dopamine transport and signalling, e.g. (DA) receptors, tyrosine hydroxylase (TH) and dopamine transporter (DAT), suggesting that they have the capacity to synthesize, take up, store and release dopamine [ 19 – 23 ]. In addition, in clinical context, PBMCs have an advantage over other tissues in SUD studies because they are readily available from the patients being studied.…”