Research
The first line of investigation the laboratory focuses on is 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).
Current HIV-1 anti-retroviral therapy, when adhered to, controls viral replication but does not eradicate the virus. Instead these drugs have been shown to have poor penetrability into certain end organs, such as the brain, due to the blood brain barrier. These therapies also have little effect on cells that have reduced viral replication, such as hematopoetic progenitor cells (HPCs) found in the bone marrow. Due to this, the bone marrow has been suggested to serve as a reservoir for latent HIV-1-infected cells and/or be 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 (HAD).
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. Previous studies in the laboratory have shown that the CD34+/CD38+ TF-1 erythromyeloid progenitor cell line can be utilized as a model to study the differentiation process of HPCs and contain MOR-1. Therefore the laboratory focuses on determining the functional relevance of MOR-1 in this model cell line and primary cells in altering HIV-1 co-receptor expression, susceptibility to HIV-1 infection, HIV-1 promoter function, and HIV-1 replication both in undifferentiated HPCs and during cytokine-induced progenitor cell differentiation. These studies are aimed at the hypothesis that this viral reservoir may be increased in patients who use heroin, which naturally breaks down to morphine in the body, and that patients on this drug in combination with cytokines that induce HPC differentiation will result in increased viral replication and reseeding of the peripheral blood and CNS from this reservoir.
The second line of investigation within 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.
Selected Publications (See all Michael Nonnemacher's publications in PubMed.)
"Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis"
Ferrucci A, Nonnemacher MR, and Wigdahl B
Advances in Virus Research, in press, 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 For Neurovirology, Electronic Publication ahead of print, DOI:10.1007/s13365-011-0037-2, 2011
"Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway"
Banerjee A, Pirrone V, Wigdahl B, and Nonnemacher MR
Biomedicine and Pharmacotherapy, Electronic Publication ahead of print, DOI:10.1016/j.biopha.2011.03.009, 2011
"Breaking Down the Barrier: The effects of HIV-1 on the Blood-Brain Barrier"
Strazza M, Pirrone V, Wigdahl B, and Nonnemacher MR
Brain Research Reviews, 1399: 96-115, 2011
"Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment"
Li L, Aiamkitsumrit B, Pirrone V, Nonnemacher MR, 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 For Neurovirology, 17(1): 92-109, 2011
"Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency type 1 subtype C LTR"
Liu Y, Nonnemacher MR, Stauff DL, Li L, Banerjee A, Irish B, Kilareski E, Rajagopalan N, Suchitra JB, Khan ZK, Ranga U, and Wigdahl B
Biomedicine and Pharmacotherapy, 64(10): 672-680, 2010
"Innate and Adaptive Factors Regulating Human Immunodeficiency Virus Type 1 Genomic Activation"
Shah S, Nonnemacher MR, Pirrone V, and Wigdahl B
The Journal of Neuroimmune Pharmacology, 5(3): 278-293, 2010
“HIV latency & reactivation: role in neuropathogenesis” in “Chemokine Receptors and NeuroAIDS: Beyond the co-receptor function and links to other neuropathologies”
Banerjee A, Nonnemacher MR, and Wigdahl B
Springer Verlag, pp 87-118, 2009
"Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage"
Kilareski EM, Shah S, Nonnemacher MR, and Wigdahl B
Retrovirology, 6: 118-140, 2009
"Molecular Mechanisms of Neurodegenerative Diseases Induced by Human Retroviruses"
Irish BP, Khan ZK, Jain P, Nonnemacher MR, Pirrone V, Rahman S, Rajagopalan N, Suchitra, JB, and Wigdahl B
American Journal of Infectious Diseases, 5:238-265, 2009
"Mortality Among HIV-infected Patients in Resource Limited Settings: A Case Controlled Analysis of Inpatients at a Community Care Center"
Rajagopalan N, Suchitra JB, Shet A, Khan ZK, Martin-Garcia J, Nonnemacher MR, Jacobson, JM, and Wigdahl B
American Journal of Infectious Diseases, 5: 226-231, 2009
"CCAAT/enhancer binding proteins and the pathogenesis of retrovirus infection"
Liu Y, Nonnemacher MR, and Wigdahl B
Future Microbiology, 4: 321-321, 2009
"IL-1β production by differentiating TF-1 bone marrow progenitor cells"
Alexaki A, Banerjee A, Kilareski E, Nonnemacher MR, and Wigdahl B
Proceedings of the 8th International Congress of Neuroimmunology, 353-359, 2007
"PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcription"
Alexaki A, Quiterio S, Liu Y, Irish B, Kilareski E, Nonnemacher MR, and Wigdahl B
DNA and Cell Biology, 26(6): 387-394, 2007
"AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation"
Grant C, Nonnemacher MR, Irish B, Alefantis T, and Wigdahl B
Journal of Leukocyte Biology, Sep; 80(3): 640-650, 2006
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