University of Nebraska Medical Center
Keywords: SIV, HIV, NeuroAIDS, Methamphetamine, CNS Dysfunction
In the News:
UNMC Today, April 21, 2014
January 10, 2013 -InterCOM, A newsletter from the College of Medicine, UNMC
July 15, 2011 -UNMC Today
March 21, 2011 - UNMC Today
July 6, 2010 - UNMC Today
May 4, 2010 - HIV and Aging Workshop
In his own words - listen to Dr. Fox discuss careers in science and his research.
Our primary work models the development of neurodegeneration leading to dementia utilizing a brain disease that results after a known stimulus, infection with HIV. Using infection of rhesus monkeys with simian immunodeficiency virus (SIV) as a model of neuroAIDS, we are studying the virology, immunology, pathology, neurobiology, and molecular basis of the resulting central nervous system (CNS) disease. Two recent examples of this work are given below.
First, using “omic” technologies, we have discovered novel biomarkers for CNS disease, leading to mechanistic insights into neurodegenerative processes. Among these is the finding of osteopontin as a marker for HIV induced dementia, as well as the correlation of increased expression of one of its receptors on monocytes, CD44v6, with SIV encephalitis. Mechanistically, we have found that osteopontin acts to increase macrophage accumulation within tissues, paralleling the increased macrophages in the brain that are responsible for HIV dementia.
Second, we have embarked on a novel project assessing whether metabolites in the cerebrospinal fluid (CSF) would be useful as candidate biomarkers. Indeed they are, and using a combination of metabolomic and transcriptomic profiling, we have identified multiple new CSF biomarkers, which led to the discovery of a distinct mechanism of SIV-induced CNS disease. This work is now expanding to encompass other CNS disorders and holds great promise in having significant basic and applied impact.
Students and postdoctoral trainees can participate in a number of the projects in Dr. Fox’s laboratory. Those interested in molecular training can join projects involved in synthesizing the combined transcriptomic, proteomic, and metabolomic data to examine pathophysiological mechanisms of disease. Those with interests in virology, immunology and/or neuroscience can help us probe the immune response to infection within the brain, and assess its effect on neuronal function. While each trainee will have an independent project, the common themes involve several members of the group.
Gaskill PJ, Zandonatti M, Gilmartin T, Head SR, and Fox HS. (2008). Macrophage derived SIV exhibits enhanced infectivity by comparison with T cell derived virus. Journal of Virology 82: 1615-1621.
Marcondes MC, Lanigan CM, Burdo TH, Watry DD, and Fox HS. (2008). Monocyte CD44v6 Correlates with the Development of Encephalitis in SIV-Infected Rhesus Macaques. Journal of Infectious Diseases 197: 1567-1576.
Marcondes MC, Sopper S, Sauermann S, Burdo TH, Watry DD, Zandonatti MA, and Fox HS. (2008). CD4 deficits and Disease Course Acceleration can be driven by a collapse of the CD8 response in SIV-infected Rhesus Macaques. AIDS 22: 1441-1432.
Wikoff WR, Pendyala G, Siuzdak G, and Fox HS. (2008). Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques. Journal of Clinical Investigation 118: 2661-2669.
Alirezaei M, Kiosses WB, Flynn CT, Brady NR, and Fox HS. (2008). Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS ONE 3: e2906.
Burdo TH, Ellis RJ, Fox HS. (2008). Osteopontin is increased in HIV-Associated Dementia. Journal of Infectious Diseases 198(5):715-722.
Marcondes MC, Watry DD, Zandonatti MA, Flynn CT, Taffe MA and Fox, HS. (2008). Chronic alcohol consumption generates a vulnerable immune environment during early SIV infection in rhesus macaques. Alcoholism: Clinical and Experimental Research 9:1583-1592.
Coutinho A, Flynn C, Burdo TH, Mervis RF, and Fox HS. (2008). Chronic Methamphetamine Induces Structural Changes in Frontal Cortex Neurons and Upregulates Type I Interferons. J. Neuroimmune Pharmacology 4:241-245.
Marcondes MC, Poling M, Watry DD, Hall D, and Fox HS. (2008). In vivo Osteopontin-induced Macrophage Accumulation is Dependent on CD44 Expression.Cellular Immunology 254(1):56-62.
Marcondes MC, Flynn C, Huitron-Rezendiz S, Watry DD, Zandonatti M, Fox HS. (2009) Early antiretroviral treatment prevents the development of central nervous system abnormalities in simian immunodeficiency virus-infected rhesus monkeys. AIDS 23(10):1187-95.
Gersten M, Alirezaei M, Marcondes MC, Flynn C, Ravasi T, Ideker T, Fox HS. (2009) An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction. J. Neurosci. 29(40): 12467-76.
Marcondes MC, Flynn C, Watry DD, Zandonatti M, Fox HS. (2010) Methamphetamine Increases Brain Viral Load and Activates Natural Killer Cells in Simian Immunodeficiency Virus-Infected Monkeys. Am J Pathol Jul;177(1):355-61.
Purnell PR, Fox HS (2013). Autophagy-mediated turnover of dynamin-related protein 1. BMC Neuroscience, 14: 86. PMCID: PMC3750610.