Dopaminergic immunomodulation drives macrophage inflammation during HIV infection

Substance use disorders (SUD) continue to be a major public health concern globally, worsening the health of
millions of people and costing hundreds of billions of dollars each year. The use of addictive substances is a
major risk factor for CNS dysfunction, and also increases risky behaviors, exposing individuals with SUD to viral
infections such as HIV. People with HIV (PWH) have a disproportionately high level of substance misuse, in
whom these substances accelerate and exacerbate the development of disease, particularly increasing the risk
for developing neurological complications (neuroHIV). Importantly, neuroHIV remains prevalent even with
antiretroviral therapy (ARV), making the treatment of neurological complications a high priority in the current era.
NeuroHIV is driven by CNS myeloid cells such as macrophages which promote neuroinflammation and are
primary targets for infection in the brain, also potentially serving as viral reservoirs.
All addictive substances increase extracellular dopamine in the CNS, exposing CNS macrophages to
aberrantly high levels of dopamine. Our lab has shown that dopamine promotes inflammation in human
macrophages and increases HIV entry into these cells. However, it remains unclear how dopamine signals in
these immune cells to drive inflammation and how these signaling pathways are exacerbated in the presence of
HIV. Dopamine canonically signals through its cognate GPCR (D1, D2, D3, D4, D5) to regulate cAMP signaling,
but in immune cells, our published data show dopamine does not activate this pathway. Instead, our data show
that dopamine signals by increasing Ca2+ flux and PKC phosphorylation, and our preliminary studies indicate
dopamine can also act on adrenergic receptors to activate Akt. This underlies the focus of this proposal, which
examines the capacity of these alternative signaling pathways to regulate dopaminergic immunomodulation.
Specifically, we hypothesize that dopamine drives macrophage inflammation through D1 dopamine
receptors by acting through alternative signaling pathways and that these mechanisms are exacerbated
in the presence of HIV.
We will test this hypothesis using a multifaceted approach employing high content imaging and analysis
to identify the specific pathways mediating dopaminergic immunomodulation in macrophages in the presence or
absence of HIV. We will use in vitro pharmacological inhibition and molecular knockdown of catecholamine
receptors (dopamine and adrenergic receptors) in both infected and uninfected macrophage models to examine
the receptors (Aim 1) and downstream intermediates (Aim 2) that mediate the effects of dopamine on
inflammation. We will use the activity of NF-kB and production of inflammatory cytokines as readouts, examining
both primary human monocyte derived macrophages and pluripotent stem cell derived macrophages. These
studies will significantly advance our understanding of the cellular mechanisms underlying the role of dopamine
and addictive substances in HIV neuropathogenesis.

Grant Number: 5F30AI179472-02
NIH Institute/Center: NIH
Principal Investigator: Breana Channer