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Amanda Brown PhD

photo of Dr. Amanda Brown

Title(s):
Assistant Professor of Neurology
Director, JHU NIMH Development Core

Appointment Phone:
410-614-4509 (p)

Primary Location:
The Johns Hopkins University
School of Medicine
Department of Neurology
Meyer Bldg, Room 6-181
600 N. Wolfe Street
Baltimore, MD 21287

Research Areas:
The JHU NIMH Research Center

Bio:

Dr. Brown received her doctoral degree from The Albert Einstein College of Medicine of Yeshiva University in Microbiology and Immunology. Her thesis work utilized genetic and molecular approaches to isolate and characterize SecA, the central regulator of the general protein secretion pathway of non- and pathogenic mycobacteria. Dr. Brown then pursued a postdoctoral fellowship in HIV-1 pathogenesis at the Aaron Diamond AIDS Research Center. At ADARC, Dr. Brown identified a multiprotein signal transducing complex of primary T-cells and macrophages that contributes to the enhanced infectivity function of HIV-1 Nef. After 3 years Dr. Brown was promoted to Research Scientist and during this phase developed the first recombinant HIV-1 replication competent macrophage-tropic reporter virus. The reporter gene, green fluorescent protein (GFP) provides a signal that HIV gene transcription has been initiated and can be detected in cells by flow cytometry and microscopic methods. Through this methodology Dr. Brown and colleagues showed that HIV-1 Nef down-regulates major histocompatibility molecules on the surface of infected macrophages, likely contributing to the ability of HIV-1 to escape detection and elimination by the immune system and persists in reservoirs.

It is the problem of HIV-1 reservoirs, particularly of the target cell, macrophages, that brought Dr. Brown to the Department of Neurology at the Johns Hopkins University School of Medicine. Macrophages are the main population of cells in the brain that are infected by HIV-1. The secretion of inflammatory and toxic substances as well as the expression of specific HIV-1 proteins can lead to the development of HIV-associated neurocognitive disorder (HAND). The availability of antiretroviral therapy has greatly diminished the occurrence of fulminant HIV encephalitis. However, the prevalence of milder forms of neuronal injury and dementia continues to increase. One hypothesis is that immune and cellular activation from HIV-macrophage reservoirs promotes neuronal injury leading to HAND. Using long-term cultures of primary monocyte-derived macrophages infected with the GFP-tagged M-tropic reporter virus, Dr. Brown and colleagues developed an in vitro model of persistent infection. They discovered that there are distinct subpopulations of infected cells, some of which remain productively infected for over 2 months, while another produces only early viral gene products such as Tat and Nef. Future studies will determine whether these phenotypes are host or viral genotype specific. In addition to these studies of viral persistence, Dr. Brown has also identified host cell factors that are differentially expressed in HIV-infected macrophages. Studies are currently in progress using small RNA-interfering technology in macrophages as well as heterologous HIV-infection culture systems to elucidate the specific role of these factors in the HIV life cycle.

About 5-10% of HIV-infected persons will develop HIV-dementia suggesting that host genetic background plays a role in the disease. It has been reported that possession of a CCL3L1 gene dosage below the ethnic group average increases susceptibility to HIV infection and the development of AIDS-associated illnesses such as dementia. Studies of DNA samples from the Northeast Atlantic AIDS Dementia Cohort (NEAD) and from the National NeuroAIDS Tissue Consortium (NNTC) are in progress to determine whether CCL3L1 gene copy number can stratify patients into distinct groups of dementia severity. In addition, collaborations with other faculty in the NeuroAIDS group are in progress to examine the role of genes involved in pathways of oxidative stress and the development of HAND.

Additional Resources:

Curriculum Vitae

 
 
 
 
 
 

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