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).
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HTLV-1 Tax Nucleocytoplasmic Shuttling
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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:
- Ahuja, J., Lepoutre, V., Wigdahl, B., Khan, Z. K., and P. Jain. Induction of proinflammatory cytokines by human T cell leukemia virus type 1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells. Biomedicine and Pharmacotherapy, 61(4): 201-208, 2007.
- Jain, P., Mostoller, K., Flaig, K., Ahuja, J., Lepoutre, V., Alefantis, T., Khan, Z. K., and B. Wigdahl. Identification of HTLV-1 Tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein. Journal of Biological Chemistry, 282(47): 34581-34593, 2007.
- Alexaki, A., Banerjee, A., Kilareski, E., Nonnemacher, M. R., and B. Wigdahl. IL-1β production by differentiating TF-1 bone marrow progenitor cells. Proceedings of the 8th International Congress of Neuroimmunology, 353-359, 2007.
- Alexaki, A., Quiterio, S., Liu, Y., Irish, B., Kilareski, E., Nonnemacher, M., and B. Wigdahl. PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcription. DNA and Cell Biology, 26(6): 387-394, 2007.
- Thakkar, N., Pirrone, V., Passic, S., Zhu, W., Kholodovych, V., Welsh, W., Rando, R. F., Labib, M. E., Wigdahl, B., and F. C. Krebs. Specific interactions between the viral co-receptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection. Antimicrobial Agents and Chemotherapy, 53(2): 631-638, 2008.
- Alexaki, A. and B. Wigdahl. HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral dissemination. PloS Pathogens, 4(12), e1000215, 2008.
- Alexaki, A., Liu, Y., and B. Wigdahl. Cellular reservoirs of HIV-1 and their role in viral persistence. Current HIV Research, 6(5): 388-400, 2008.
- Pavlovic, J., Floros, J., Phelps, D., Wigdahl, B., Welsh, P., Weisz, J., Shearer, D., Leure du Pree, A., Myers, R., and Mary K. Howett. Differentiation of xenografted human fetal lung parenchyma. Early Human Development, 84(3): 181-193, 2008.
- Rajagopalan, N., Suchitra, J. B., Shet, A., Khan, Z. K., Martin-Garcia, J., Nonnemacher, M. R., Jacobson, J. M., and B. Wigdahl. Mortality among HIV-infected patients in resource limited settings: A case controlled analysis of inpatients at a community care center. American Journal of Infectious Disease, 5: 226-231, 2009.
- Irish, B. P., Khan, Z. K., Jain, P., Nonnemacher, M. R., Pirrone, V., Rahman, S., Rajagopalan, N., Suchitra, J. B., and B. Wigdahl. Molecular mechanisms of neurodegenerative diseases induced by human retroviruses. American Journal of Infectious Diseases, 5: 283-265, 2009.
- Jain, P., Manuel, S., Khan, Z. K., Ahuja, J., and B. Wigdahl. DC-SIGN mediates cell-free infection and transmission of human T cell leukemia virus type 1. Journal of Virology, 83(21): 1054-1059, 2009.
- Kilareski, E. M., Shah, S., Nonnemacher, M. R., and B. Wigdahl. Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage. Retrovirology, 6: 118, 2009.
- Thakkar, N., Pirrone, V., Passic, S. R., Keogan, S., Zhu, W., Kholodovych, V., Welsh, W., Rando, R., Labib, M., Wigdahl, B., and F. C. Krebs. Persistent interactions between the biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection. Antimicrobial Agents and Chemotherapy, in press, 2010.
- Banerjee A., Nonnemacher M. R., and B. Wigdahl. HIV latency & reactivation: role in neuropathogenesis in Chemokine Receptors and NeuroAIDS: Beyond the co-receptor function and links to other neuropathologies. Springer Verlag, in press, 2010.
- Rahman, S., Quann, K., Wigdahl, B., Pandya, D., Manuel, S., Acheampong, E., Khan, Z. K., and P. Jain. Regulation of HTLV-1 promoter formatted in the context of chromatin in T cells. Virology, submitted, 2010.
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