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Warner C. Greene: focuses on the pathogenic interplay of the HIV-1 and HTLV-I human retroviruses with immune cells. PDF Print E-mail
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Thursday, 26 August 2010 23:11

My laboratory focuses on the pathogenic interplay of the HIV-1 and HTLV-I human retroviruses with immune cells. Infection of human hosts with these retroviruses produces contrasting diseases within the CD4 subset of T lymphocytes, specifically the Acquired Immune Deficiency Syndrome (AIDS) with HIV-1 and the Adult T-cell Leukemia (ATL) with HTLV-1. Their studies explore the molecular biology of the HIV Vif, Nef and Vpr gene products as well as the transforming properties of HTLV-I Tax. More recently, we have begun to study HIV and HTLV-1 Env-mediated fusion and the mechanisms underlying transmission of HIV across the female genital mucosa.


We continue to also pursue our longstanding interest in the biology of the NF-kB/Rel family of transcription factors, which serve as "master regulators" of the immune and inflammatory responses. These studies currently focus on the role of these transcription factors as major antagonists of HIV latency.

Significance
My laboratory seeks to understand the molecular basis for HIV and HTLV-I retroviral pathogenesis. Through the insights gained from these studies, we hope to contribute to the development of new therapeutic approaches for these fatal retrovirus-induced diseases. Similarly, our studies of NF-kB are not only aimed at unraveling how this powerful transcription factor is regulated, but also at developing new strategies for intervening in unwanted inflammatory and immune reactions mediated by NF-kB.

Approaches
Due to the broad scope of experimental questions, we employ a wide range of molecular, biochemical, cell biological and immunological techniques to study HIV and HTLV-I pathogenesis. Individuals completing training in the laboratory routinely acquire expertise in all of these areas. Increasingly, we are utilizing transgenesis and gene disruption approaches to study the function of specific genes in vivo. Our studies often take advantage of the outstanding core services offered at the Gladstone Institutes including cores in Virology, Immunology, Genomics, Flow Cytometry, Microscopy, Histology, Transgenesis and Gene Disruption.

Contributions
A list of scientific advances made by members of the laboratory and the relevant citations for this work is presented in the "Past Contributions" section of this home page.

Some questions addressed in ongoing studies
  • How does Vif overcome the potent innate antiviral activity of APOBEC3G?

  • How does HIV Nef accelerate viral pathogenesis?

  • How does HIV Vpr induce G2 cell cycle arrest and does such derangement of the cell cycle occur in HIV infected patients?

  • What are the signals that promote nuclear import of the HIV preintegration complex?

  • How does HTLV-I Tax induce T cell transformation and is its sustained expression required for the maintenance of the transformed state?

  • How does HIV cross the mucosal surface of the female genital tract and do different HIV clades display different efficiencies in this process?

  • Do HIV virions fuse with higher efficiency to specific subsets of human CD4 T cells and dendritic cells?

  • What are the various cellular mechanisms and post-translational modifications responsible for regulating the expression and action of the eukaryotic NF-kB/Rel family of transcription factors?

  • What cellular signaling process contributes to the role that NF-kB/Rel transcription factors play in HIV latency?

  • What role do the various NF-kB/Rel transcriptional regulators play in regulating human embryonic stem cell (hESC) pluripotency versus differentiation?

  • What are the events that regulate the actvation of NF-kB/Rel in the brain and how does the action of this factor impact on normal versus disease-related neuronal function?

Selected Recent Publications

  • Santiago ML, Montano M, Benitez R, Messer RJ, Yonemoto W, Chesebro B, Hasenkrug KJ, Greene WC (2008) APOBEC3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science 321:1343–1346.

  • Cavrois M, Neidleman J, Greene WC (2008) The Achilles heel of the Trojan horse model of HIV trans-infection. PLoS Path. 4:e1000051.

  • Chiu Y-L, Greene WC (2008) The APOBEC3 cytidine deaminases: An innate defensive network opposing exogenous retroviruses and endogenous retroelements. Ann. Rev. Immunol. 26:317–353.

  • Chen L-f, Greene WC (2007) Regulation of nuclear NF-kB action: A key role for post-translational modification. In: Handbook of Transcription Factor NF-kB (Ghosh S, ed.), CRC Press, Boca Raton, FL, pp. 87–105.

  • Soros VB, Yonemoto W, Greene WC. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Path. 3:e15.

  • Cavrois M, Neidleman J, Kreisberg JF, Greene WC. In vitro derived dendritic cells trans-infect CD4 T cells primarily with surface-bound HIV-1 virions. PLoS Path. 3:e4.

  • Stopak KS, Chiu Y-L, Kropp J, Grant RM, Greene WC. Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J. Biol. Chem. 282:3539–3546.

  • Chiu YL, Witkowska HE, Hall SC, Santiago M, Soros VB, Esnault C, Heidmann T, Greene WC (2006) High-molecular mass APOBEC3G complexes restrict Alu retrotransposition. PNAS 103:15588–15593.

  • Zimmerman ES, Sherman MP, Blackett JL, Neidleman JA, Kreis C, Mundt P, Williams SA, Warmerdam M, Kahn J, Hecht FM, Grant RM, de Noronha CMC, Weyrich AS, Greene WC, Planelles V (2006) HIV-1 Vpr induces DNA replication stress in vitro and in vivo. J. Virol. 80:10407–10418.

  • Chandrasekar B, Mummidi S, Mahimainathan L, Pael DN, Bailey SR, Imam SZ, Greene WC, Valente AJ (2006) Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kB- and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J. Biol. Chem. 281:15099–15109.

  • O’Mahony A, Raber J, Foehr E, Montano M, Han V, Lu S, Kwon H, LeFevour A, Chakraborty-Sett S, Greene WC (2006) NF-kB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity. Mol. Cell Biol. 26:7283–7298.

  • Soros VB, Greene WC (2006) APOBEC3G and HIV-1: Strike and Counterstrike. Curr. Inf. Dis. Rep. 8:317–323.

  • Chiu Y-L, Greene WC (2006) Multifaceted antiviral actions of APOBEC3 cytidine deaminases. Trends Immunol. 27:291–297.

  • Kreisberg JF, Yonemoto W, Greene WC (2006) Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high-molecular-mass APOBEC3G complex formation. J. Exp. Med. 203:865–870.

  • Cavrois M, Neidleman J, Kreisberg JF, Fenard D, Callebaut C, Greene WC (2006) Human immunodeficiency virus fusion to dendritic cells declines as cells mature. J. Virol. 80:1992–1999.

  • Chiu Y-L, Greene WC (2006) APOBEC3 cytidine deaminases: Distinct antiviral actions along the retroviral life cycle. J. Biol. Chem. 281:8309–8312.

  • de Noronha C, Greene WC (2007) Retroviruses and the Nucleus. In: Hiscox JA (Ed.), Viruses and the Nucleus, John Wiley & Sons, Ltd., Chicester, UK, pp 89–128.

  • Greene WC (2007) Molecular biology of HIV: Implications for new therapies. In: Global HIV/AIDS Medicine (Sande M, Lange J, Volberding P, Greene WC, eds.), Elsevier, Philadelphiapp 23–38.

  • Williams SA, Chen L-f, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC (2006) NF-kB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–149.

  • Chiu Y-L, Soros VB, Kreisberg JF, Stopak K, Yonemoto W, Greene WC. Cellular APOBEC3G restricts HIV-1 infection in resting CD4 T cells. Nature 435:108–114, 2005.
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  • Greene WC. The brightening future of HIV therapeutics. Nat. Immunol. 5:867–871, 2004.
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  • Stopak K, de Noronha C, Yonemoto W, Greene WC. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol. Cell 12:591–601, 2003.
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  • Chen LF, Mu Y, Greene WC. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kB. EMBO J. 21:6539–6548, 2002.
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  • Greene WC, Peterlin BM. Charting HIV's remarkable voyage through the cell: Basic science as a passport to future therapy. Nat. Med. 8:673–680, 2002.
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  • Chen L-f, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kB action is regulated by reversible acetylation. Science 293:1653–1657, 2001.
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  • de Noronha CMC, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294:1105–1108, 2001.

  • Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signaling providing a potential mechanism for protecting the infected host cell. Nature 410:834–838, 2001.
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