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  • This connection is supported by studies in

    2022-01-13

    This connection is supported by studies in the SIV macaque model of HIV, where treatment with methamphetamine, which greatly enhances CNS dopamine levels (Truong, 2005); increased mimosine viral load. Methamphetamine also increased expression of the HIV co-receptor CCR5 in CNS macrophages, thereby enhancing the susceptibility of these cells to infection (Marcondes, 2010, Najera, 2016, Gaskill, 2014). Ongoing studies in our lab have also examined the effects of dopamine exposure on HIV infection in vitro using primary human macrophages. These studies use dopamine concentrations (10−10 M–10−5 M) present in the CNS during drug abuse, homeostatic and pathologic conditions (Koob, 1992, Venton, 2003, Gonon and Buda, 1985, Kimmel et al., 2005, Schiffer, 2003, Zachek, 2010, Xi, 2009). They show that exposing macrophages to elevated dopamine increases their susceptibility to infection. The effect on macrophages is critical to the development of NeuroHIV, as myeloid cells are thought to be the primary drivers of HIV neuropathogenesis. Primary MDM were infected with HIVYU2 or HIVBaL, HIV strains that use the CCR5 co-receptor, which is the main co-receptor involved in the infection of macrophages. Infections in the presence of dopamine, or specific agonists for D1-like (SKF38393) and D2-like (Quinpirole) dopamine receptors show that activation of all dopamine receptor subtypes increases HIV entry into macrophages. Pretreatment with the pan-dopamine receptor antagonist flupenthixol, or the CCR5 antagonist TAK779, blocked the effects of dopamine on HIV entry, indicating that the mechanism is dependent on both CCR5 and dopamine-receptors (Coley, 2015, Arthos, 2000). The involvement of both D1- and D2-like dopamine receptors suggests activation of a signaling pathway common to both subtypes, although canonically, different dopamine receptor subtypes mediate opposing effects. However, both subtypes of dopamine receptors can also induce Ca2+ release from the endoplasmic reticulum (So, 2009), which has been connected with HIV infection in a number of experiments. Interaction of HIV-gp120 with CCR5 induces Ca2+ mobilization via Gαq (Liu, 2000, Melar et al., 2007, Arai and Charo, 1996, Harmon and Ratner, 2008), and Ca2+ flux is an essential step for in HIV entry in an astrocyte model of infection (LaVoie and Hastings, 1999; Harmon and Ratner, 2008). Our own studies in DR1 and DR2-transfected HEK293 cells show that dopamine receptor activation potentiates Ca2+ mobilization Gaskill et al., 2014. Together, this indicates that Ca2+ release may be the common mechanism by which dopamine receptor activation enhances entry and suggests that PLC-mediated Ca2+ mobilization may be a novel therapeutic target in the prevention of HIV infection. Although our data point to a Ca2+ mediated mechanism, dopamine-mediated potentiation of HIV infection act through other mechanisms, such as the NF-kB mediated effects shown in T-cells by Rohr and colleagues (Rohr, 1999, Scheller, 2000). Enhanced oxidative stress is another possible mechanism, as dopamine oxidizes to form free radicals and reactive dopamine quinones (Pyo, 2008), and studies show HIV LTR driven reporter expression and reactivation of latent HIV in T-cells can be mediated by the interaction of reactive oxygen species (ROS) and NF-kB activation (Yang, 2009, Fazal, 1997). The effects of dopamine in ACH-2 cells resulted from treatment with pharmacologic levels of dopamine (6–10 × 10−5 M), which increased HIV production via an oxidative mechanism. This effect was prevented by the addition of the antioxidant glutathione, indicating that the reactivation of HIV by dopamine was due to oxidative stress (Kumar, 2006). All these data come from T-cells, suggesting this cell type may be more vulnerable to virologic effects induced by oxidative stress, perhaps because macrophages require exposure to ROS for proper polarization and effector function (Tan, 2016, Dichtl, 2017). While our studies show 24-h exposure to dopamine is not cytotoxic in macrophages (Gaskill et al., unpublished results), other studies show murine bone-marrow derived macrophages (BMDM) exposed to pharmacologic dopamine (5 × 10−6 M) for 24 h did increase expression of oxidative stress markers (Cole, 1998). Taken together, these data suggest that dopamine may enhance HIV infection through several different effector pathways, and that these might differ with distinct cell types.