Research Interests

The current focus of my laboratory is on both Genomics and Proteomics of HIV-1 and HTLV-1 infected cells. HIV-1 is the etiological agent of AIDS and HTLV-1 is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HIV-1 infected cells are associated with apoptosis and cell death, whereas HTLV-1 infection is associated with anti-apoptosis or malignancy.

The microarray analysis of infected cells is routinely done in our lab with 12,000 to 30,000 gene arrays from Affymetrix or custom printed material. Data is analyzed based on alterations in pathways including signal transduction, transcription, translation, cell cycle checkpoints, and apoptosis machinery. Through this functional genomics and various bioinformatic tools, we have recently been able to design cell cycle inhibitor drugs that specifically destroy HIV-1 infected cells (Wang et al., Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. J Virol. 2001 Aug;75(16):7266-79). A similar approach is currently being tested on HTLV-1, HHV-8 (Kaposia Sarcoma associated virus), Hepatitis C, and other DNA viruses such as CMV, and EBV infected cells.

The Proteomic approach analysis, for the first time, detects host polypeptides that are altered upon infection with HIV-1 or HTLV-1, as well as detecting all post-translational modifications associated with viral open reading frames (orfs). For this, 12 orfs from HIV-1 and 5 orfs from HTLV-1 are the subject of study. Viral proteins are subjected to biochemical separation methods, such as standard and immunoaffinity chromatography, and analyzed using MALDI-TOF or Tandem Mass Spec MS/MS spectrometer. We believe by understanding true post translational changes apparent only in infected host cells, along with data analysis using bioinformatic tools, we will be able to design specific drugs against these viral orfs, and have a clear understanding of what site(s) of each of these proteins are available for antibody binding or cytotoxic T-cell (CTL) reactions. This approach will lead to designing of true antigenic domains for obtaining both innate and acquired immunity needed for AIDS vaccines.

Finally, through the use of bioinformatics, specifically collecting and storing relevant sequences, alignment of multiple DNA, RNA and protein sequences, RNA secondary structure predictions, phylogenic and epidemiological prediction based on patient samples and field isolates, data base searching of both public and private sectors, and protein classification and structure prediction, we are able to decipher the complex code of both HIV-1 and HTLV-1 as well as many other virally infected cells.

Selected Publications (Total of 55 PubMed Entries):

1. 
   Agbottah E, Zhang N, Dadgar S, Pumfery A, Wade JD, Zeng C, Kashanchi F. Inhibition of HIV-1 virus replication using small soluble Tat peptides. Virology. 2005 Nov 11; [Epub ahead of print]
2. Brady J, Kashanchi F. Tat gets the "Green" light on transcription initiation. Retrovirology. 2005 Nov 9;2(1):69 [Epub ahead of print]
3. Haffar O, Dubrovsky L, Lowe R, Berro R, Kashanchi F, Godden J, Vanpouille C, Bajorath J, Bukrinsky M. Oxadiazols: a new class of rationally designed anti-human immunodeficiency virus compounds targeting the nuclear localization signal of the viral matrix protein. J Virol. 2005 Oct;79(20):13028-36.
4. Kashanchi F, Brady JN. Transcriptional and post-transcriptional gene regulation of HTLV-1. Review. Oncogene. 2005 Sep 5;24(39):5938-51.
   
5. Ammosova T, Jerebtsova M, Beullens M, Lesage B, Jackson A, Kashanchi F, Southerland W, Gordeuk VR, Bollen M, Nekhai S. Nuclear targeting of protein phosphatase-1 by HIV-1 TAT protein. J Biol Chem. 2005 Aug 29; [Epub ahead of print]
   
6. Ammosova T, Berro R, Kashanchi F, Nekhai S. RNA interference directed to CDK2 inhibits HIV-1 transcription. Virology. 2005 Oct 25;341(2):171-8. Epub 2005 Aug 8.
7. Liang WS, Maddukuri A, Teslovich TM, de la Fuente C, Agbottah E, Dadgar S, Kehn K, Hautaniemi S, Pumfery A, Stephan DA, Kashanchi F. Therapeutic targets for HIV-1 infection in the host proteome. Retrovirology. 2005 Mar 21;2(1):20.
8. Agbottah E, de La Fuente C, Nekhai S, Barnett A, Gianella-Borradori A, Pumfery A, Kashanchi F. Antiviral Activity of CYC202 in HIV-1-infected Cells. J Biol Chem. 2005 Jan 28;280(4):3029-42.
9. Kylene Kehn, Cynthia de la Fuente, Katharine Strouss, Reem Berro, Hua Jiang, John Brady, Renaud Mahieux, Anne Pumfery, Maria Elena Bottazzi, Fatah Kashanchi. The HTLV-I Tax Oncoprotein Targets the Retinoblastoma (Rb) Protein For Proteasomal Degradation. Oncogene. 2005 Jan 20;24(4):525-40
10. Meisheng Zhou, Longwen Deng, Vincent Lacoste, Hyeon Ung Park, Anne Pumfery, Fatah Kashanchi, John N. Brady, and Ajit Kumar. Coordination of transcription factor phosphorylation and histone methylation by the P-TEFb kinase during HIV-1 transcription. J Virol. 2004 Dec;78(24):13522-33.
11. Ghedin E, Pumfery A, De La Fuente C, Yao K, Miller N, Lacoste V, Quackenbush J, Jacobson S, Kashanchi F. Use of a multi-virus array for the study of human viral and retroviral pathogens: gene expression studies and ChIP-chip analysis. Retrovirology. 2004 May 25;1(1):10.
12. Wu K, Bottazzi ME, De La Fuente C, Deng L, Gitlin SD, Maddukuri A, Dadgar S, Li H, Vertes A, Pumfery A, Kashanchi F. Protein profile of Tax-associated complexes. J Biol Chem. 2004 Jan 2; 279(1): 495-508.
13. Zhou M, Deng L, Kashanchi F, Brady JN, Shatkin AJ, Kumar A. The Tat/TAR-dependent phosphorylation of RNA polymerase II C-terminal domain stimulates cotranscriptional capping of HIV-1 mRNA. Proc Natl Acad Sci U S A. 2003 100(22): 12666-71.
14. Pumfery A, Deng L, Maddukuri A, de la Fuente C, Li H, Wade JD, Lambert P, Kumar A, and Kashanchi F. Chromatin Remodeling and Modification during HIV-1 Tat-activated Transcription. Current HIV Research. 2003, 1, 261-274.
15. de la Fuente C, Maddukuri A, Kehn K, Baylor SY, Deng L, Pumfery A, and Kashanchi F. Pharmacological Cyclin-dependent Kinase Inhibitors as HIV-1 Antiviral Therapeutics. Current HIV Research. 2003, 1, 131-152
16. Deng L, Ammosova T, Pumfery A, Kashanchi F, and Nekhai S. HIV-1 Tat interaction with RNA polymerase II CTD and a dynamic association with CDK2 induces CTD phosphorylation and transcription from HIV-1 promoter. J Biol Chem. 2002, 277:33922-33929
17. de la Fuente C, Santiago F, Deng L, Eadie C, Zilberman I, Kehn K, Maddukuri A, Baylor S, Wu K, Lee CG, Pumfery A, and Kashanchi F. Gene expression profile of HIV-1 tat expressing cells: a close interplay between proliferative and differentiation signals. BMC Biochem 2002, 3:14,
18. Furia B, Deng L, Wu K, Baylor S, Kehn K, Li H, Donnelly R, Coleman T, Kashanchi F. Enhancement of Nuclear Factor-kappa B Acetylation by Coactivator p300 and HIV-1 Tat Proteins. J Biol Chem. 2002, 277:4973-80