Michael Nonnemacher

Michael Nonnemacher

Assistant Professor, Microbiology and Immunology
Assistant Director, Center for Molecular Virology and Neuroimmunology, Institute for Molecular Medicine and Infectious Disease

Ph.D., Pennsylvania State University College of Medicine, 2004

245 N. 15th Street
Mail Stop 1013A, Room 18304
Philadelphia, PA 19102
Tel: 215-762-4154
Fax: 215-762-1955
Email: michael.nonnemacher@drexelmed.edu

Keywords:

HIV-1, SIV, Drugs of abuse, Monocytes, C/EBP, Sp, LTR

Research Interests:

In general the laboratory is focused on studying the impact of genetic variation and drugs of abuse on HIV-1 and SIV replication and pathogenesis. Studies within the laboratory focus on identifying transcription factor binding sites within the HIV-1 and SIV long terminal repeat, the promoter for HIV-1 and SIV transcription, to characterize new sites important for transcription and replication of these viruses in different cell types. Specifically the CCAAT/enhancer binding protein (C/EBP) binding sites within the LTR are examined due to their importance to replication of these viruses in cells of the monocyte/macrophage lineage. It is this cell lineage that is believed to be a site of viral latency and responsible for carrying most of the virus found in the central nervous system (CNS) to the brain. Investigators in the laboratory also study the impact of genetic variation within these sites to determine how this impacts their transcription and replication ability and correlates with immune and CNS disease progression.

A new line of investigation within the laboratory examines the impact of drugs of abuse, especially opioids, on HIV-1 disease and bone marrow hematopoiesis. Opioid drugs like morphine exert their addictive and analgesic effects either by activation of the hypothalamic-pituitary-adrenal (HPA) axis or directly via opioid receptors. Besides being expressed in the central nervous system, the three pharmacologic subtypes (mu, lambda and kappa) of opioid receptors have been identified on a host of immune cells. Several lines of evidence now indicate that opioids, in particular morphine, act as a cofactor in enhancing susceptibility to HIV-1 infection in immune cell populations as well as modulating innate, humoral, and cell-mediated immunity by acting through the mu opioid receptor-1 (MOR-1). It has been suggested that the bone marrow may serve as a source of newly HIV-1-infected monocytes which traffic to the peripheral blood and reseed the brain contributing to the pathological symptoms associated with the development of HIV-associated dementia (HIVD). Interestingly, CD34+/CD38- progenitor cells within the bone marrow are refractile to HIV-1 infection, probably due to their low level expression of HIV-1 co-receptors, CXCR4 and CCR5. However as they mature into lineage committed cells, they become more susceptible. We have shown that the CD34+/CD38+ TF-1 erythromyeloid progenitor cell line can be utilized as a model to study the differentiation process of hematopoietic progenitor cells. Given these observations, we have undertaken studies to identify the presence of the mu opioid receptor-1 on the TF-1 bone marrow progenitor cell line and to determine the functional relevance of these receptors in altering HIV-1 co-receptor expression, susceptibility to HIV-1 infection and replication during cytokine-induced TF-1 progenitor cell differentiation.

Publications:

Ross, H. L., Nonnemacher, M. R., Hogan, T., Quiterio, S. J., Henderson, A., Krebs, F., and B. Wigdahl. Interaction between CAAT enhancer binding protein and cyclic AMP response element binding protein 1 regulates human immunodeficiency virus type 1 transcription in cells of the monocyte/macrophage lineage. Journal of Virology, 75: 1842-1856, 2001.
Dhanak, D., Duffy, K.J., Johnston, V.K., Lin-Goerke, J., Darcy, M., Shaw, A.N., Gu, B., Silverman, C., Gates, A.T., Nonnemacher, M.R., Earnshaw, D.L., Casper, D.J., Kaura, A., Baker, A., Greenwood, C., Gutshall, L.L., Maley, D., DelVecchio, A., Macarron, R., Hofman, G.A., Alnoah, Z., Cheng, H.Y., Chan, G., Khandekar, S., Keenan, R.M., and R.T. Sarisky. Identification and biological characterization of heterocyclic inhibitors of the hepatits C virus RNA-dependent RNA polymerase. J Biol Chemistry, 277(41): 38322-38327, 2002.
Hogan, T. H., Nonnemacher, M. R., Krebs, F. C., Henderson, A., and B. Wigdahl. HIV-Vpr binding to HIV-1 LTR C/EBP cis-acting elements and adjacent regions is sequence-specific. Biomed Pharmacother, 57: 41-48, 2003.
Nonnemacher, M. R., Hogan, T. H., Quiterio, S. J., Wigdahl, B., Henderson, A., and F. C. Krebs. Identification of binding sites for members of the CCAAT/enhancer binding protein transcription factor family in the simian immunodeficiency virus long terminal repeat. Biomed Pharmacother, 57: 34-40, 2003.
Burdo, T. H., Nonnemacher, M.R., Irish, B. P., Choi, C. H., Krebs, F. C., Gartner, S., and B. Wigdahl. High affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-κB sites within the HIV-1 LTR correlate with HIV-1 associated dementia. DNA and Cell Biology, 23(4): 261-269, 2004.
Nonnemacher, M. R., Irish, B. P., Liu, Y., Mauger, D., and B. Wigdahl. Specific sequence configurations of HIV-1 LTR G/C box array result in altered recruitment of Sp isoforms and correlate with disease progression. Journal of Neuroimmunology, 157: 39-47, 2004.
Grant, C., Nonnemacher, M. R., Jain, P., Pandya, D., Irish, B., Williams, S. C., and B. Wigdahl. CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type I long terminal repeat activation. Virology, 348(2): 354-369, 2006.
Yao, J., Grant, C., Harhaj, E., Nonnemacher, M. R., Alefantis, T., Martin, J., Jain, P. and B. Wigdahl. Regulation of human T cell leukemia virus type I gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III. DNA and Cell Biology, 25(5): 262-276, 2006.
Grant, C., Nonnemacher, M. R., Irish, B., Alefantis, T., and B. Wigdahl. AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation. Journal of Leukocyte Biology, Sep; 80(3): 640-650, 2006.
Alexaki, A., Quiterio, S., Liu, Y., Irish, B., Kilareski, E., Nonnemacher, M. R., 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.
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.
Haine, V., Fischer-Smith, T., Ke, Y., Kogan, M., Liu, Y., Nonnemacher, M. R., Wigdahl, B., Sawaya, B. E., and J. Rappaport. HIV-1Vpr upregulates M-CSF in primary human macrophages: role of C/EBPβ and the glucocorticoid receptor pathway. Journal of Virology, in revision, 2007.
Liu, Y., Nonnemacher, M. R., Alexaki, A., Kilareski, E., and B. Wigdahl. C/EBP cis-acting elements downstream of the lentiviral long terminal repeat affects HIV-1 transcription in cells of the monocyte/macrophage lineage. DNA Cell Biology, in revision, 2007.
Alexaki, A., Quiterio, S. J., Nonnemacher, M. R., Liu, Y., Banerjee, A., Li, L., Miller, S., Kilareski, E., and B. Wigdahl. Modeling bone marrow progenitor cell differentiation and susceptibility to HIV-1 infection. J. Leukocyte Biology, in revision, 2007.
Irish, B. P., Nonnemacher, M. R., and B. Wigdahl. Genetic Variation and HIV-induced neurologic disease. In “Microbial Infections of the Neurologic System” in the series, “Infections Agents and Pathogenesis.” Edited by: A. Seyfang, H. Friedman, and M. Bendinelli. Springer Publishers, invited review, submitted for publication, 2007.