Johns Hopkins School of Medicine

Mechanisms of Neuroinflammation in Disease 

Research in the Brown lab focuses on how breach of the blood-brain-barrier by viral pathogens like the human immunodeficiency virus type 1 (HIV-1), alters brain homeostasis. Central to this research is acquiring a detailed mechanistic understanding of the pathways leading to sustained neuroinflammation. HIV-1 robustly infects microglia and macrophages, but not neurons and to a lesser extent, astrocytes.

Today, antiviral treatment, has transformed HIV infection allowing people to live longer. However, HIV exacerbates many of the comorbid conditions associated with aging and up to 50% of people with HIV can experience neurologic complications. 

None of the current therapies block HIV transcription. The Brown lab is testing the hypothesis that ongoing systemic low-level HIV gene expression drives chronic activation of pro-inflammatory signaling which impairs cognition. The ultimate goals of the research are to identify and understand the key gene expression networks involved. With such knowledge, new treatments to ameliorate HIV-associated cognitive comorbidities can be developed. 

The lab’s experimental approach to modeling HIV-induced neuroinflammation include the use of physiologically relevant primary cell culture models, humanized mice (hu-mice) that reflect HIV systemic or brain infection, and the use of human brain tissues to validate findings. Well-validated molecular, as well as leading-edge tools in neuroscience including rodent PET- and MRI-neuroimaging, sn-RNA-seq, multicolor immunofluorescence and associated analytic tools like Imaris are used. The lab has developed protocols to safely assess memory, locomotor and motivational behaviors in the immunodeficient hu-mice models. 

Research over the past five years in the Brown lab has implicated the multifunctional protein, osteopontin (OPN), which is encoded by the SPP1 gene, as a sensor and regulator of neuroinflammation in HIV-hu-mice. OPN/SPP1 has long been described in neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, multiple sclerosis (MS), and fronto-tempro dementia as a putative predictive biomarker.  However, except for MS, there remains a profound lack of insight into OPN/SPP1’s mechanistic function (s) in the brain. Exciting recent findings from the Brown laboratory and their collaborators indicate that OPN/SPP1 is a master regulator of neuroinflammatory signaling. Ongoing studies are investigating the impact of OPN/SPP1 on cognition, dopaminergic-glial signaling, white matter integrity, and immune cell trafficking.