Dopamine increases HIV entry into macrophages by increasing calcium release via an alternative signaling pathway

Dopaminergic dysfunction has long been connected to the development of HIV infection in the CNS. Our previous data showed that dopamine increases HIV infection in human macrophages by increasing the susceptibility of primary human macrophages to HIV entry through stimulation of both D1-like and D2-like receptors. These data suggest that, in macrophages, both dopamine receptor subtypes may act through a common signaling mechanism. To define better the mechanism(s) underlying this effect, this study examines the specific signaling processes activated by dopamine in primary human monocyte-derived macrophages (hMDM). In addition to confirming that the increase in entry is unique to dopamine, these studies show that dopamine increases HIV entry through a PKA insensitive, Ca²⁺ dependent pathway. Further examination demonstrated that dopamine can signal through a previously defined, non-canonical pathway in human macrophages. This pathway involves both Ca²⁺ release and PKC phosphorylation, and these data show that dopamine mediates both of these effects and that both were partially inhibited by the G_q/11 specific inhibitor YM-254890. Studies have shown that G_q/11 preferentially couples to the D1-like receptor D5, indicating an important role of the D1-like receptors in mediating these effects. These data indicate a role for Ca²⁺ flux in the HIV entry process, and suggest a distinct signaling mechanism mediating some of the effects of dopamine in macrophages. Together, the data indicate that targeting this alternative dopamine signaling pathway might provide new therapeutic options for individuals with elevated CNS dopamine suffering from NeuroHIV.