Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Abstract

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

“…In contrast to its role in preventing sepsis, macrophage exposure to dopamine may increase susceptibility to HIV [20, 21]. Macrophages are the main cell type in the CNS that are infected with HIV, and recent studies showed that dopamine treatment of human peripheral blood monocyte-derived macrophages led to a two-fold increase in CCR5-mediated HIV entry and increased HIV replication.…”

Role of Autophagy in HIV Pathogenesis and Drug Abuse

“…Compared with non-users, HIV patients who are drug users exhibit increased frequency of HIV-encephalitis [135]. Some of the drugs, such as cocaine and methamphetamine, exert addictive and reinforcing effects via increased extracellular dopamine level in the brain, while altered activity of dopamine and dopamine receptors has been implicated in the pathogenesis of HIV-1 in terms of viral entry and replication [112,136]. Other factors that facilitate HIV viral entry includes disruption in the integrity of blood-brain barrier (BBB).…”

Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport

“…In the early stage of HIV infection, increased levels of DA and decreased DA turnover are found in the cerebrospinal fluid of therapy-naïve HIV patients with asymptomatic infection12, which may contribute to decreased levels of DA in DA-rich brain regions81314 in the advanced stages of HIV infection. Importantly, HIV-induced elevated levels of extracellular DA in the CNS can stimulate viral replication in human macrophages within DA-rich brain regions151617, resulting in viral protein release. It is commonly accepted that viral replication and proteins within the CNS are correlated with the persistence of HIV-related neuropathology and subsequent neurocognitive deficits18192021.…”