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High-content screening analysis of dopamine-mediated changes in human macrophages in the context of HIV infection
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High-content screening analysis of dopamine-mediated changes in human macrophages in the context of HIV infection

Yi Rong
Master of Science (M.S.), Drexel University
Nov 2019
DOI:
https://doi.org/10.17918/6baw-8216
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Abstract

Dopamine--Physiological effect Macrophages HIV infections Pharmacology Physiology
High-content screening (HCS) is a relatively new methodology by which we are able to address biological questions using immunocytochemistry and large-scale, data-driven analyses. This technique has become more accessible due to the, advances in computer science and technology. Utilizing this advanced technique provides a more robust and diverse analysis of large scale data sets. In this project, we are using high-content screening to examine two mechanisms by which the neurotransmitter dopamine could influence HIV neuropathogenesis. Although HIV is one of the most devastating viruses in the world, its effects on the central nervous system (CNS), are poorly understood. HIV enters the CNS within 8 days after initial infection, where the virus targets primarily myeloid cells such as perivascular macrophages and microglia. The infection of these populations leads to neuroinflammation and HIV-associated neurocognitive disorders (HAND). Drug abuse is a major comorbidity in HIV infection, and all drugs of abuse increase dopamine, so the impact of dopamine on HIV neuropathogenesis is very important. Using the high content imaging technique, we found that dopamine does not alter the localization of CCR5 within lipid raft and non-lipid raft regions. However, we demonstrated that CCR5(3A9) but not CCR5(2D7) is preferentially localized to lipid raft domains, which could lead to a new target for HIV treatment by targeting CCR5(3A9) in the lipid raft. We also used high content screening to show that dopamine treatment increases the number of macrophages within a population that have elevated nuclear NF-[kappa]B. This suggests dopamine increases the number of macrophages which could produce a more robust inflammatory response. This could be beneficial to the future therapeutic strategies for treating inflammation. Together, these studies provide new insight into the mechanisms by which dopamine influences HIV infection and demonstrate the utility and power of high content screening.

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