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|Nov. 2018||Basova, L., et al. (2018). "Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection." PLoS One 13(6): e0199861.|
About This Paper:
HIV- infected individuals develop various levels of neurological deficits that are associated with an inflammatory process in the brain. These are are aggravated by co-morbidities such as drugs of abuse. For instance, Methamphetamine (Meth) is a highly addictive drug that increases brain viral load, and this happens in correlation with a higher number of CCR5-expressing HIV-target cells. CCR5 is a chemokine receptor involved in increasing inflammation, but is also a co-receptor for viral entry into cells. CCR5-expressing myeloid cells are the main targets of HIV in the CNS. Thus, the identification of factors and mechanisms that impact the expression of CCR5 in the brain and elsewhere is critical, as it may affect infection. Using an in vitro system, we found that Meth directly regulates the abundance and nuclear translocation of transcription factors with binding sites in the CCR5 promoter. However, the main factor that acts at the epigenetic level on the CCR5 gene promoter is Dopamine (DA), a neurotransmitter that is produced primarily in brain regions that are rich in dopaminergic neurons. In Meth abusers, DA is present at very high levels in the brain. The effect of DA in enhancing innate immune CCR5 transcription was mediated mainly by DA receptor (DRDs), particularly the DRD4 subtype. The selective stimulation of the DRD1 subtype, on the other hand, can suppress CCR5 expression in this myeloid cell system, with potential implications for therapy. Importantly, DA increased CCR5 expression on the cell surface at acute time-points, and increased HIV infection in vitro. Our data suggests that the exposure of myeloid cells to Meth affect the number of HIV targets by modulating CCR5 expression, through a combination of DA-dependent epigenetic modifications and DA–independent increase of transcription factors. Other stimulant drugs that increase DA may affect HIV through a similar mechanism.