Retroviruses have been implicated as causative agents in immunologic dysfunction, malignancy, and a number of progressive neurologic disorders. The overall goal of the research program is to identify molecular mechanisms involved in the pathogenesis of these viral pathogens and to develop strategies to diagnose, prevent, and treat human disease caused by these devastating agents. Ongoing research is focused in three major programmatic areas utilizing molecular, cellular, and modeling technologies involving (1) protein structure and function studies using fluorescence-activated flow cytometry, laser capture and deconvolution fluorescence microscopy, (2) molecular genomics and proteomic strategies, (3) DNA sequencing and genotype analyses, (4) molecular modeling strategies to facilitate design of novel therapeutic agents, (5) DNA-protein biochemistry, (6) methods to assess transcriptional control mechanisms, (7) in vitro cell culture models, (8) viral replication studies utilizing biocontainment safety level 3 (BSL-3) facilities, (9) in vivo animal model systems, and (10) xenografting, cellular trafficking, and quantitative assessment procedures to identify specific uninfected and infected cell populations.
In the first programmatic area, the molecular mechanisms involved in regulating gene expression of human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS) and the progressive neurologic disorder, HIV-dementia (HIVD), is under exploration. Specifically, the laboratory focuses on the impact of retrovirus genetic variation, signaling pathways, cellular differentiation processes and viral transactivators on critical DNA-protein interactions involved in regulating HIV transcription in cells of monocyte-macrophage origin, including CD34+ precursor cells in the bone marrow and peripheral blood. In addition to defining the transcription regulatory mechanisms that may be critical to the etiology of HIVD, studies are also focused on defining signature sequences in the viral long terminal repeat (LTR) and genes encoding HIV regulatory proteins (Tat and Vpr) that may provide information useful in developing predictive tools to track the development of neurologic disease and therapeutic targets
In the second area of investigation, molecular modeling strategies and other experimental approaches are being used to develop therapeutic strategies to prevent sexual transmission of HIV. These studies have led to the identification of a family of compounds that interfere with the interaction of HIV-1 gp120 with the receptor (CD4) and the coreceptors (CXCR4 and CCR5).
HTLV-1 Tax Nucleocytoplasmic Shuttling
In the third area of investigation, the role that a selected group of cellular transcription factors (Sp1/Sp3, C/EBP, AP-1, and ATF/CREB) play in regulating Tax-mediated transactivation of the human T cell lymphotropic virus type I (HTLV-I) LTR during hematopoiesis and during development and activation of cells of the monocyte-macrophage origin and other lineages of cells important in cell-mediated immune response to HTLV infection is under investigation. Studies are also in progress to identify nuclear and cytoplasmic proteins involved in nuclear export and secretion of the HTLV-1 oncoprotein Tax. These studies will also identify Tax domains integrally involved in these processes. Defining these molecular interactions will be important to developing new therapeutic strategies to prevent HTLV-I-associated neurologic disease.
Selected Publications (See all Brian Wigdahl's publications in PubMed.)
"Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1"
Pirrone V, Passic SR, Wigdahl B, and FC Krebs
Virology Journal, 9(1): 33, 2012
"Macrophage colony stimulating factor regulation by nuclear factor kappa B: A relevant pathway in human immunodeficiency virus type 1 infected macrophages"
Kogan M, Haine V, Ke Y, Wigdahl B, Fischer-Smith T, and J Rappaport
DNA and Cell Biology, 31(3): 278-288, 2012
"Extracellular human immunodeficiency virus type 1 viral protein R causes a reduction in ATP and glutathione levels in an astrocytic cell line resulting in a compromised antioxidant reservoir"
Ferrucci A, Nonnemacher MR, Cohen EA, and B Wigdahl
Virus Research, 167(2): 358-369, 2012
"Deployment of the HIV-1 protein arsenal: Combatingthe host to enhance viral transcription and providing targets for therapeutic development"
Dahiya S, Nonnemacher MR, and B Wigdahl
J. General Virology, 93: 1151-1172, 2012
"Impact of Tat genetic variation on HIV-1 disease"
Li L, Dahiya S, Kortagere S, Cunningham D, Pirrone V, Nonnemacher M, and B Wigdahl
Advances in Virology, Volume 2012, Article ID 123605, 2012
"Substance abuse, HIV-1 and hepatitis"
Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, and B Wigdahl
Current HIV Research, 10(7): 557-571, 2012
"Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis"
Ferrucci A, Nonnemacher MR, and B Wigdahl
Advances in Viral Research, 81: 165-199, 2011
"Role of Mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis"
Banerjee A, Strazza M, Wigdahl B, Pirrone V, Meucci O, and Nonnemacher MR
Journal of Neurovirology, 17(4):291-302, 2011
"Cellular phenotype impacts human immunodeficiency virus type 1 viral protein R subcellular localization"
Ferrucci A, Nonnemacher MR and Wigdahl B
Virology Journal, 8(1):397, 2011
"Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway"
Banerjee A, Pirrone V, Wigdahl B, and Nonnemacher M
Biomedicine and Pharmacotherapy, 65(4):293-297, 2011
"Breaking Down the Barrier: The effects of HIV-1 on the blood-brain barrier"
Strazza M, Pirrone V, Wigdahl B, and Nonnemacher M
Brain Research, 1399:96-115, 2011
"Combinatorial approaches to the prevention and treatment of HIV-1 infection"
Pirrone V, Thakkar-Rivera N, Jacobson J, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, 55(5):1831-1842, 2011
"Development of co-selected single nucleotide polymorphisms in the viral promoter procedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment"
Li L, Aiamkitsumrit B, Pirrone V, Nonnemacher M, Wojno A, Passic S, Flaig K, Kilareski E, Blakey B, Ku J, Parikh N, Shah R, Martin-Garcia J, Moldover B, Servance L, Downie D, Lewis S, Jacobson JM, Kolson D, and Wigdahl B
Journal of NeuroVirology, 17:92-109, 2011
"Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection"
Rahman S, Khan ZK, Wigdahl B, Jennings SR, Tangy F, and Jain P
Journal of Immunology, 186(1):390-402, 2011 |