Making Discoveries that Make a Difference

Fatah Kashanchi; PhD

Laboratory of Molecular Virology

Biosketch

Dr. Kashanchi received his PhD in 1990 in Microbiology with emphasis on retrovirus gene expression. He worked with Dr. C. Wood on HIV-1 gene expression, who was a student of Nobel Laurette Dr. Tongawa (1987) on B-cell development and gp120 ELISA. He then moved to Washington, DC for his Postdoctoral and Research Associate fellowship at National Cancer Institute, National Institutes of Health from 1991-1998. He was tenured at the George Washington University medical school as a full Professor in 2004. He moved to GMU as director of research in 2010 and stayed at that position until 2013.

Research Interests

Human retroviruses, biodefense viral agents, Cell cycle, host-pathogen interactions, small molecule and peptide inhibitors against transcription machinery, RNAi machinery and its components, proteomics and metabolomics, humanized mouse models, and extracellular vesicles, including exosomes.

Research Program

Some of the current research in the Kashanchi Lab is focused on defining transcriptional and chromatin mediated regulation of HIV-1 and HTLV-1 infected cells. Our studies have resulted in novel concepts regarding promoter-bound proteins that regulate all events of mRNA biogenesis (including capping, elongation, termination, poly-A addition, splicing), nuclear-cytoplasmic transport, and activation of nonsense mRNA degradation. Among biothreat agents, the Kashanchi lab is interested in Rift Valley fever virus (RVFV), Ebola, and Venezuela Equine Encepalitis virus (VEEV) replication in vitro and in vivo. Additional research includes investigation into Ebola VP40-containing exosomes and defining crucial host-pathogen interactions that are imperative to pathogenesis.

Transcription and Chromatin: Number of chromatin remodeling complexes belonging to SWI/SNF have been studied in relation to both HIV-1 and HTLV-1 transcription. One specific complex termed PBAF is responsible for activation of both viral promoters in the presence of the activators Tat and Tax. Furthermore, one specific component, namely Baf170, is highly regulated and expressed in retrovirus-infected cells. Nucleosome positioning of promoter elements specifically at +1 region indicates changes in histone content and post-translational modifications on both promoters. These changes are regulated by the PBAF complex and acetylated viral proteins. The lab has also published on 2 compounds that inhibit HIV-1 transcription through regulation of CDK9/cyclin T1.

RNAi Machinery: Work in the Kashanchi lab has shown that critical differences exist in the microRNA machinery in T-cells versus monocyte/macrophages. Monocytes do not have a central protein called DICER and differentiated macrophages have low levels of DICER protein. Furthermore, the presence of complete RNAi machinery in T-cells contributes to presence of viral miRNA, which in turn controls latency and suppresses viral gene expression through epigenetic means. An example of such viral miRNA is shown in a stem and loop structure called TAR which is present at high levels in infected cells (105 copies). The effect of the non-coding RNA is on both viral and cellular genes, which contribute to anti-apoptotic nature of this RNA.

Inhibitors of transcription and other related pathways: The Kashanchi lab has published and focused on a number of CDK inhibitors, as well as, other host signaling pathways including GSK. The ATP analogs that constitute the majority of the CDK inhibitors are easy to make and fairly selective in HIV-1 infected cells. The reason for the selectivity is the nature of the kinases is altered after infection and the substrates that they phosphorylate are dramatically different. Furthermore, many of the drug inhibitors enhance the level of short transcripts (TAR), which contribute to further specificity on HIV-1 and cellular promoters.

RVFV and VEEV: The research focuses on the use of Reverse phase Protein MicroArray (RPMA) and other phosphoproteomic methods to decipher signal transduction modulation following viral infection that contribute to infection and replication of these two viruses in multiple host cells. Efforts are underway to define relevant biomarkers in both infected and uninfected cells using standard mass spectrometry andnovel metabolomics approaches (Laser Ablation Electrospray Ionization Mass Spectrometry developed by colleagues at the George Washington University). These approaches can potentially identify inhibitors of host activated pathways that contribute to pathogenesis.

Extracellular Vesicles and HIV-1 Pathogenesis: In recent years, the Kashanchi Lab has started focusing on Extracellular vesicles (i.e., exosomes), primarily those from latent virally infected cells. These latent HIV-1 infected cells remain in the body for a long period of time despite the administration of supressive antiretroviral therapeutics. The latent cells can persist through the life of a person in viral reservoirs (i.e., CNS cells). Latently infected cells can produce extracellular vesicles that carry markers of the infection including viral RNA and protein sequences specific to a given virus. Exosomes are small vesicles, 30–120 nm in length, released from all cell types in the body, can be found in various bodily fluids, such as semen and urine and are transported through the bloodstream and the lymphatic system. They are formed by inward folding of the endosomal membrane to form multivesicular bodies (MVBs), a process carried out by the endosomal sorting complex.  They have recently found distinct markers (RNA and proteins) from T-cell vs. Myeloid exosomes that may control recipient cell gene expression (Narayanan, et al. 2013). The Kashanchi lab, for the first time, showed that viral release and exosome release have overlapping biogenesis in the ESCRT pathway.  For instance, HIV-1 latent cells utilize ESCRT-I for viral release, and ESCRT-II for exosomal release.  Using in vitro and in vivo (both patient samples and animal models), the lab has found that exosomes from HIV-1 infected cells carry short non-coding RNAs (i.e., TAR) which regulate TLR3 and other pathways in the recipient cells. This data also implies that endogenous retroviruses may have a similar mode of action in their gene expression by expressing short non-coding RNAs that no only regulate the donor cells, but also the recipient cells through the exosomes transfer pathway.  The infected cells (in presence of antiretroviral drugs or innate immune molecules) still secret exosomes that contain viral products including TAR, TAR-gag RNA, and Nef protein (Naranyan, et al. 2013, Sampey, et al. 2016, DeMarino et al. 2018). These findings implicate extracellular vesicles in the pathogenesis of HIV-1 in latent viral reservoirs and suggest that extracellular vesicles and their cargo may contribute to the chronic CNS inflammation observed in long-term, antiretroviral-treated HIV-1 patients. Further work by the Kashanchi in the field of extracellular vesicle research includes the identification of novel compounds to inhibit extracellular vesicle release and mitigate downstream pathogenesis.

Ebola virus VP40 and Exosomes: Ebola virus (EBOV) infection can cause Ebola virus disease (EVD) in humans and nonhuman primates (NHPs), potentially resulting in severe hemorrhagic fever characterized by cytokine storm, bystander lymphocyte apoptosis, coagulopathy, and mortality rates of up to 90% in those affected.  Patients who have been fortunate enough to recover from EVD suffer long-lasting sequelae, as well as potential persistence and recurrence of infection many months after convalescence.  With use of many of the techniques we routinely utilize for exosomal isolation and analysis, our lab has previously shown that the EBOV matrix protein (VP40) becomes packaged into exosomes.  Through mechanistic studies into the packaging of VP40 into exosomes, we have demonstrated that VP40 is able to migrate into the nucleus of host cells and thereby affect the transcription of Cyclin D1 at its promoter.  Upregulation of Cyclin D1 protein thereby was shown to result in an increased rate of cell cycling in VP40-producing cells, which in turn impacted the Endosomal Sorting Complexes Required for Transport (ESCRT) pathway and subsequent exosomal biogenesis, thus resulting in the packaging of VP40 into exosomes.  Phosphorylation of VP40 was likewise shown in host cells by cdk2/Cyclin complexes tied to cell cycle.  VP40-containing exosomes were shown to be greater in size and density as compared to control exosomes and were shown by LC-MS/MS to contain numerous helicases and RNA binding proteins such as hnRNPs.  Cytokine analysis also demonstrated that VP40 exosomes were upregulated in several cytokines known to be important during EVD, including TGF-β1, IFN-γ, IL-15, and MCP-1.  Treatment of recipient immune cells (T-cells and monocytes) with VP40-containing exosomes resulted in significant cell death by apoptosis, similar to the bystander lymphocyte apoptosis observed in fatal cases of EVD.  We have additionally shown that in both host VP40 exosome donor and recipient cells, there is a downregulation of RNAi machinery components Dicer and Drosha, which may potentially be connected to the induction of apoptosis in recipient immune cells.  Finally, we have tested the potential utility of cell cycle blockers (Ribociclib and Fascaplysin) and FDA-approved antibiotics (Oxytetracycline) to inhibit the biogenesis of damaging exosomes from VP40-producing cells.  Future studies will be focused on the mechanisms of induction of apoptosis in recipient immune cells, investigation of the potential integration of other viral proteins into exosomes (i.e. such as GP and NP proteins) and their downstream effects, and testing of potential therapeutics to avert the death of immune cells during acute infection, thereby potentially preventing the destruction of surveilling immune cell populations during EVD, which may ultimately allow for the host to control and overcome EBOV infection (Pleet et al., 2016; 2017; 2018).

Humanized mouse models: The Kashanchi lab utilizes a number of humanized animal models, including Rag double knockout, as well as, NOD/SCID animals to study HIV-1 and HTLV-1 infections. Various organs from infected animals are used to define viral tropism and evaluate how small molecule and peptide inhibitors effectively contribute to inhibition of virus replication in these humanized animals. The lab also has established an HIV-1 latent model for long term studies.

Relevant Publications from the past 10 years (selected from 210 PubMed citations; h-index 55)

  • Pleet ML, Branscome H, DeMarino C, Pinto DO, Zadeh MA, Rodriguez M, Sariyer IK, El-Hage N, Kashanchi F. Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time. Front Cell Infect Microbiol. 2018 Oct 18;8:362. doi: 10.3389/fcimb.2018.00362. eCollection 2018. Review.
  • Ojha CR, Rodriguez M, Lapierre J, Muthu Karuppan MK, Branscome H, Kashanchi F, El-Hage N. Complementary Mechanisms Potentially Involved in the Pathology of Zika Virus.Front Immunol. 2018 Oct 15;9:2340. doi: 10.3389/fimmu.2018.02340. eCollection 2018. Review.
  • Bella R, Kaminski R, Mancuso P, Young WB, Chen C, Sariyer R, Fischer T, Amini S, Ferrante P, Jacobson JM, Kashanchi F, Khalili K. Removal of HIV DNA by CRISPR from Patient Blood Engrafts in Humanized Mice. Mol Ther Nucleic Acids. 2018 Sep 7;12:275-282. doi: 10.1016/j.omtn.2018.05.021. Epub 2018 Jun 19.
  • Pleet ML, Erickson J, DeMarino C, Barclay RA, Cowen M, Lepene B, Liang J, Kuhn JH, Prugar L, Stonier SW, Dye JM, Zhou W, Liotta LA, Aman MJ, Kashanchi F, Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular Vesicles. J Infect Dis. 2018 Aug 30. doi: 10.1093/infdis/jiy472.
  • Anderson MR, Pleet ML, Enose-Akahata Y, Erickson J, Monaco MC, Akpamagbo Y, Velluci A, Tanaka Y, Azodi S, Lepene B, Jones J, Kashanchi F, Jacobson S. Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes.Clin Transl Med. 2018 Aug 27;7(1):24. doi: 10.1186/s40169-018-0204-7.
  • DeMarino C, Pleet ML, Cowen M, Barclay RA, Akpamagbo Y, Erickson J, Ndembe N, Charurat M, Jumare J, Bwala S, Alabi P, Hogan M, Gupta A, Hooten NN, Evans MK, Lepene B, Zhou W, Caputi M, Romerio F, Royal W 3rd, El-Hage N, Liotta LA, Kashanchi Antiretroviral Drugs Extracellular Vesicles from HIV-1-Infected Cells. Sci Rep. 2018 May 16;8(1):7653. doi: 10.1038/s41598-018-25943-2.
  • Anderson M, Kashanchi F, Jacobson S. Role of Exosomes in Human Retroviral Mediated Disorders. J Neuroimmune Pharmacol. 2018 Apr 14. doi: 10.1007/s11481-018-9784-7. [Epub ahead of print] Review.
  • Li K, Rodosthenous RS, Kashanchi F, Gingeras T, Gould SJ, Kuo LS, Kurre P, Lee H, Leonard JN, Liu H, Lombo TB, Momma S, Nolan JP, Ochocinska MJ, Pegtel DM, Sadovsky Y, Sánchez-Madrid F, Valdes KM, Vickers KC, Weaver AM, Witwer KW, Zeng Y, Das S, Raffai RL, Howcroft TK. Advances, challenges, and opportunities in extracellular RNA biology: insights from the NIH exRNA Strategic Workshop .JCI Insight. 2018 Apr 5;3(7). pii: 98942. doi: 10.1172/jci.insight.98942. [Epub ahead of print] Review.
  • Meltzer B, Dabbagh D, Guo J, Kashanchi F, Tyagi M, Wu Y. Tat controls transcriptional persistence of unintegrated HIV genome in primary human macrophages. Virology. 2018 May;518:241-252. doi: 10.1016/j.virol.2018.03.006. Epub 2018 Mar 15.
  • Haque S, Sinha N, Ranjit S, Midde NM, Kashanchi F, Kumar S. Monocyte-derived exosomes upon exposure to cigarette smoke condensate alter their characteristics and show protective effect against cytotoxicity and HIV-1 replication.Sci Rep. 2017 Nov 23;7(1):16120. doi: 10.1038/s41598-017-16301-9.
  • Lin X, Kumari N, DeMarino C, Kont YS, Ammosova T, Kulkarni A, Jerebtsova M, Vazquez-Meves G, Ivanov A, Dmytro K, Üren A, Kashanchi F, Nekhai S. Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03. Oncotarget. 2017 Aug 7;8(44):76749-76769. doi: 10.18632/oncotarget.19999. eCollection 2017 Sep 29.
  • Hu G, Witwer KW, Bond VC, Haughey N, Kashanchi F, Pulliam L, Buch S. Proceedings of the ISEV symposium on “HIV, NeuroAIDS, drug abuse & EVs”. J Extracell Vesicles. 2017 Mar 10;6(1):1294360. doi: 10.1080/20013078.2017.1294360. eCollection 2017.
  • Rodriguez M, Lapierre J, Ojha CR, Estrada-Bueno H, Dever SM, Gewirtz DA, Kashanchi F, El-Hage N. Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes. Viruses. 2017 Jul 28;9(8). pii: E201. doi: 10.3390/v9080201.
  • Ojha CR, Lapierre J, Rodriguez M, Dever SM, Zadeh MA, DeMarino C, Pleet ML, Kashanchi F, El-Hage N. Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications. Viruses. 2017 Jul 6;9(7). pii: E176. doi: 10.3390/v9070176. Review.
  • Poveda E, Freeman ML. Hot News: Exosomes as New Players in HIV Pathogenesis – New Data from the IAS 2017. AIDS Rev. 2017 Oct-Dec;19(3):173-175.
  • Akpamagbo YA, DeMarino C, Pleet ML, Schwab A, Rodriguez M, Barclay RA, Sampey G, Iordanskiy S, El-Hage N, Kashanchi HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency. Curr Pharm Des. 2017 Jun 22. doi: 10.2174/1381612823666170622101319.
  • Barclay RA, Schwab A, DeMarino C, Akpamagbo Y, Lepene B, Kassaye S, Iordanskiy S, Kashanchi Exosomes from uninfected cells activate transcription of latent HIV-1.J Biol Chem. 2017 Jul 14;292(28):11682-11701. doi: 10.1074/jbc.M117.793521. Epub 2017 May 23. Erratum in: J Biol Chem. 2017 Sep 8;292(36):14764.
  • DeMarino C, Kashanchi Presence of Viral microRNA in Extracellular Environments. EBioMedicine. 2017 Jun;20:9-10. doi: 10.1016/j.ebiom.2017.05.008. Epub 2017 May 5.
  • Barclay RA, Pleet ML, Akpamagbo Y, Noor K, Mathiesen A, Kashanchi F. Isolation of Exosomes from HTLV-Infected Cells. Methods Mol Biol. 2017;1582:57-75. doi: 10.1007/978-1-4939-6872-5_5.
  • Pleet ML, DeMarino C, Lepene B, Aman MJ, Kashanchi The Role of Exosomal VP40 in Ebola Virus Disease. DNA Cell Biol. 2017 Apr;36(4):243-248. doi: 10.1089/dna.2017.3639. Epub 2017 Feb 8. Review.
  • Pleet ML, Mathiesen A, DeMarino C, Akpamagbo YA, Barclay RA, Schwab A, Iordanskiy S, Sampey GC, Lepene B, Nekhai S, Aman MJ, Kashanchi Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction. Front Microbiol. 2016 Nov 7;7:1765. eCollection 2016.
  • Aman MJ, Kashanchi. Zika Virus: A New Animal Model for an Arbovirus. PLoS Negl Trop Dis. 2016 May 5;10(5):e0004702. doi: 10.1371/journal.pntd.0004702. eCollection 2016 May.
  • Ahsan NA, Sampey GC, Lepene B, Akpamagbo Y, Barclay RA, Iordanskiy S, Hakami RM, Kashanchi Presence of Viral RNA and Proteins in Exosomes from Cellular Clones Resistant to Rift Valley Fever Virus Infection. Front Microbiol. 2016 Feb 11;7:139. doi: 10.3389/fmicb.2016.00139. eCollection 2016.
  • Iordanskiy S, Kashanchi. Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells. AIDS Res Hum Retroviruses. 2016 Feb;32(2):120-4. doi: 10.1089/AID.2016.0006.
  • Sardo L, Iordanskiy S, Klase Z, Kashanchi F,HIV-1 Nef blocks autophagy in human astrocytes. Cell Cycle. 2015;14(24):3781-2. doi: 10.1080/15384101.2015.1105700.
  • Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC, Casares S, Garcia JV, Hasenkrug KJ, Kashanchi F, Kitchen SG, Klein F, Kumar P, Luster AD, Poluektova LY, Rao M, Sanders-Beer BE, Shultz LD, Zack JA. Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Res Hum Retroviruses. 2016 Feb;32(2):109-19. doi: 10.1089/AID.2015.0258.
  • Sampey GC, Saifuddin M, Schwab A, Barclay R, Punya S, Chung MC, Hakami RM, Zadeh MA, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S, Kashanchi F, Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA. J Biol Chem. 2016 Jan 15;291(3):1251-66. doi: 10.1074/jbc.M115.662171. Epub 2015 Nov 9.
  • Schwab A, Meyering SS, Lepene B, Iordanskiy S, van Hoek ML, Hakami RM, Kashanchi F,Extracellular vesicles from infected cells: potential for direct pathogenesis. Front Microbiol. 2015 Oct 20;6:1132. doi: 10.3389/fmicb.2015.01132. eCollection 2015. Review.
  • Iordanskiy S, Van Duyne R, Sampey GC, Woodson CM, Fry K, Saifuddin M, Guo J, Wu Y, Romerio F, Kashanchi Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology. 2015 Jul 14;485:1-15. doi: 10.1016/j.virol.2015.06.021. [Epub ahead of print]
  • Tyagi M, Iordanskiy S, Ammosova T, Kumari N, Smith K, Breuer D, Ilatovskiy AV, Kont YS, Ivanov A, Üren A, Kovalskyy D, Petukhov M, Kashanchi F, Nekhai S. Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1. Retrovirology. 2015 Jul 16;12:63. doi: 10.1186/s12977-015-0190-4.
  • Sahu G, Farley K, El-Hage N, Aiamkitsumrit B, Fassnacht R, Kashanchi F, Ochem A, Simon GL, Karn J, Hauser KF, Tyagi M. Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR. Virology. 2015 Sep;483:185-202. doi: 10.1016/j.virol.2015.03.036. Epub 2015 May 15.
  • Guendel I, Iordanskiy S, Sampey GC, Van Duyne R, Calvert V, Petricoin E, Saifuddin M, Kehn-Hall K, Kashanchi F, Role of Bruton’s tyrosine kinase inhibitors in HIV-1-infected cells. J Neurovirol. 2015 Feb 12. [Epub ahead of print].
  • Turpin J, Journo C, Ko NL, Sinet F, Carpentier A, Galioot A, Edwards D, Vandamme AM, Gazzolo L, Duc Dodon M, Gessain A, Kashanchi F, Balansard I, Lacoste R, Mahieux R, Discovery and characterization of auxiliary proteins encoded by type 3 simian T-cell lymphotropic viruses. J Virol. 2015 Jan 15;89(2):931-51. doi: 10.1128/JVI.02150-14. Epub 2014 Oct 29.
  • Chen H, Zhao Y, Li H, Zhang D, Huang Y, Shen Q, Van Duyne R, Kashanchi F, Zeng C, Liu S, Break CDK2/Cyclin E1 interface allosterically with small peptides. PLoS One. 2014 Oct 7;9(10):e109154. doi: 10.1371/journal.pone.0109154. eCollection 2014.
  • Kumari N, Iordanskiy S, Kovalskyy D, Breuer D, Niu X, Lin X, Xu M, Gavrilenko K, Kashanchi F, Dhawan S, Nekhai S, Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase IκB-α expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription. Antimicrob Agents Chemother. 2014 Nov;58(11):6558-71. doi: 10.1128/AAC.02918-14. Epub 2014 Aug 25.
  • Jaworski E, Narayanan A, Van Duyne R, Shabbeer-Meyering S, Iordanskiy S, Saifuddin M, Das R, Afonso PV, Sampey GC, Chung M, Popratiloff A, Shrestha B, Sehgal M, Jain P, Vertes A, Mahieux R, Kashanchi F, Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. J Biol Chem. 2014 Aug 8;289(32):22284-305. doi: 10.1074/jbc.M114.549659. Epub 2014 Jun 17.
  • Jaworski E, Saifuddin M, Sampey G, Shafagati N, Van Duyne R, Iordanskiy S, Kehn-Hall K, Liotta L, Petricoin E 3rd, Young M, Lepene B, Kashanchi F, The use of Nanotrap particles technology in capturing HIV-1 virions and viral proteins from infected cells. PLoS One. 2014 May 12;9(5):e96778. doi: 10.1371/journal.pone.0096778. eCollection 2014.
  • Amaya M, Voss K, Sampey G, Senina S, de la Fuente C, Mueller C, Calvert V, Kehn-Hall K, Carpenter C, Kashanchi F, Bailey C, Mogelsvang S, Petricoin E, Narayanan A, The role of IKKβ in Venezuelan equine encephalitis virus infection. PLoS One. 2014 Feb 19;9(2):e86745. doi: 10.1371/journal.pone.0086745. eCollection 2014
  • Sampey GC, Meyering SS, Asad Zadeh M, Saifuddin M, Hakami RM, Kashanchi F, Exosomes and their role in CNS viral infections. J Neurovirol. 2014 Jun;20(3):199-208. doi: 10.1007/s13365-014-0238-6. Epub 2014 Feb 28.
  • Napier TC, Chen L, Kashanchi F, Hu XT, Repeated cocaine treatment enhances HIV-1 Tat-induced cortical excitability via over-activation of L-type calcium channels. J Neuroimmune Pharmacol. 2014 Jun;9(3):354-68. doi: 10.1007/s11481-014-9524-6. Epub 2014 Feb 25.
  • Fleming A, et al., The carrying pigeons of the cell: exosomes and their role in infectious diseases caused by human pathogens. Pathog Dis. 2014 Jul;71(2):109-20. doi: 10.1111/2049-632X.12135. Epub 2014 Feb 24.
  • Narayanan, A., et al., Exosomes derived from HIV-1 infected cells contain TAR RNA. J Biol Chem, 2013.
  • Klase, Z.A., G.C. Sampey, and F. Kashanchi, Retrovirus infected cells contain viral microRNAs. Retrovirology, 2013. 10: p. 15.
  • Sampey, G.C., et al., Complex role of microRNAs in HTLV-1 infections. Front Genet, 2012. 3: p. 295.
  • Van Duyne, R., et al., Effect of mimetic CDK9 inhibitors on HIV-1-activated transcription. J Mol Biol, 2013. 425(4): p. 812-29.
  • Chung, M.C., et al., Bacillus anthracis-derived nitric oxide induces protein S-nitrosylation contributing to macrophage death. Biochem Biophys Res Commun, 2013. 430(1): p. 125-30.
  • Tonry, J.H., et al., In vivo murine and in vitro M-like cell models of gastrointestinal anthrax. Microbes Infect, 2013. 15(1): p. 37-44.
  • Narayanan, A., et al., Curcumin inhibits Rift Valley fever virus replication in human cells. J Biol Chem, 2012. 287(40): p. 33198-214.
  • Van Duyne, R., et al., Localization and sub-cellular shuttling of HTLV-1 tax with the miRNA machinery. PLoS One, 2012. 7(7): p. e40662.
  • Narayanan, A., et al., Use of ATP analogs to inhibit HIV-1 transcription. Virology, 2012. 432(1): p. 219-31.
  • Austin, D., et al., p53 Activation following Rift Valley fever virus infection contributes to cell death and viral production. PLoS One, 2012. 7(5): p. e36327.
  • Kehn-Hall, K., et al., Modulation of GSK-3beta activity in Venezuelan equine encephalitis virus infection. PLoS One, 2012. 7(4): p. e34761.
  • Al-Harthi, L. and F. Kashanchi, Mechanisms of HIV-1 latency post HAART treatment area. Curr HIV Res, 2011. 9(8): p. 552-3.
  • Tyagi, M. and F. Kashanchi, New and novel intrinsic host repressive factors against HIV-1: PAF1 complex, HERC5 and others. Retrovirology, 2012. 9: p. 19
  • Duyne, R.V., et al., Humanized mouse models of HIV-1 latency. Curr HIV Res, 2011. 9(8): p. 595-605.
  • Van Duyne, R., et al., Varying modulation of HIV-1 LTR activity by Baf complexes. J Mol Biol, 2011. 411(3): p. 581-96.
  • Kehn-Hall, K., et al., Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors. Virology, 2011. 415(1): p. 56-68.
  • Carpio, L., et al., microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection. J RNAi Gene Silencing, 2010. 6(1): p. 386-400.
  • Van Duyne R, Guendel I, Narayanan A, Gregg E, Shafagati N, Tyagi M, Easley R, Klase Z, Nekhai S, Kehn-Hall K, Kashanchi F. Varying Modulation of HIV-1 LTR Activity by BAF Complexes. J Mol Biol. 2011 Aug 19;411(3):581-96.
  • Kehn-Hall K, Guendel I, Carpio L, Skaltsounis L, Meijer L, Al-Harthi L, Steiner JP, Nath A, Kutsch O, Kashanchi F. Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors. Virology. 2011 Jun 20;415(1):56-68.
  • Carpio L, Klase Z, Coley W, Guendel I, Choi S, Van Duyne R, Narayanan A, Kehn-Hall K, Meijer L, Kashanchi F. microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection. J RNAi Gene Silencing. 2010;6(1):386-400. PMCID: 20628499.
  • Coley W, Van Duyne R, Carpio L, Guendel I, Kehn-Hall K, Chevalier S, Narayanan A, Luu T, Lee N, Klase Z, Kashanchi F. Absence of DICER in monocytes and its regulation by HIV-1. J Biol Chem. 2010 Oct 15;285(42):31930-43.
  • Easley R, Carpio L, Dannenberg L, Choi S, Alani D, Van Duyne R, Guendel I, Klase Z, Agbottah E, Kehn-Hall K, Kashanchi F. Transcription through the HIV-1 nucleosomes: Effects of the PBAF complex in Tat activated transcription. Virology. 2010;405(2):322-333. PMCID: 20599239.
  • Kashanchi F, Kehn-Hall K Novel insights into transcriptional elongation: ubiquitination of HEXIM1 and p-TEFb activity. Cell Cycle. 2009 Aug 15;8(16):2485. PMCID: PMC Journal – In Process
  • Zhou M, Huang K, Jung KJ, Cho WK, Klase Z, Kashanchi F, Pise-Masison CA, Brady JN. Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9 at threonine 29. J Virol. 2009 Jan;83(2):1036-44. PMCID: PMC2612389
  • Van Duyne R, Easley R, Wu W, Berro R, Pedati C, Klase Z, Kehn-Hall K, Flynn EK, Symer DE, Kashanchi F. Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR.Retrovirology. 2008 May 22, 5:40. PMCID: PMC2412914
  • Berro R, Pedati C, Kehn-Hall K, Wu W, Klase Z, Even Y, Geneviere AM, Ammosova T, Nekhai S, Kashanchi F. CKD13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. J. Virol. 2008 Jul; 82 (14): 7155-66. PMCID: PMC2446983
  • Van Duyne R, Cardenas J, Easley R, Wu W, Kehn-Hall K, Klase Z, Mendez S, Zeng C, Chen H, Saifuddin M, Kashanchi F. Effect of transcription peptide inhibitors on HIV-1 replication. Virology. 2008 Jul 5; 376(2): 308-22.
  • Klase Z, Kale P, Winograd R, Gupta MV, Heydarian M, Berro R, McCaffrey T, Kashanchi F. HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol. 2007 Jul 30;8(1):63

Grants

Some of the major fundings grants from Kashanchi lab:

An NIH R01 grant on HIV neuropathogenesis realted to exosomes containing HIV non-coding RNAs. Our data indicates that infected cells under cART still secret TAR associated exosmes and that these exosomes activate the naïve recipient cells resulting in unwanted proinflammatory signals. These activities will be reversed with use of inhibitors and tested in both an in vitro BBB model and humanized latent model of HIV infection.

An NIH R01 grant on Tat peptide derivatives (mimetics) inhibitors that could potentially inhibit virus replication both in cell culture and humanized animal models. The understanding of how HIV-1 Tat manipulates the transcription machinery will aid in designing better Tat inhibitors of mimetic nature.

An NIH R21 grant on the effect of chromatin remodeling complex SWI/SNF that influence HIV-1 transcription. Specifically the role of Tat- SWI/SNF (Tat-PBAF) complex in chromatin remodeling at the HIV-1 LTR in infected cell lines and PBMC infected cells are being investigated.

An NIH R21 grant on the effect the HIV viral miRNA on the virus genome and host transcription machinery.  The virus has a multi-step life cycle that revolves around the transcriptional control of the virus as regulated by interaction between the viral Tat protein and an RNA element known as the transactivation response (TAR) element. Kashanchi lab has recently demonstrated that TAR RNA is utilized by proteins involved in RNA interference (RNAi) and is processed into a viral microRNA (miRNA) that drives remodeling of the viral LTR, leading to heterochromatin formation (transcription silencing).

An NIH R21 grant on the effect of GSK-3 inhibitor BIO on neuroAIDS and its important implications in HAND. The short term goal of the research is to determine if BIO and derivatives could be used as a potential HAND therapeutic.

An NIH collaborative grant with the Washington DC CFAR on basic science related to HIV.  The mission of the Basic Science Core is to develop, refine, and provide training and services to HIV/AIDS investigators in DC for the assays used to evaluate and quantify HIV replication and gene expression, characterize HIV disease using immunologic, genomics and proteomics approaches, and facilitate drug development by providing small animal models of HIV disease.

Dr. Kashanchi is the co-host and co-organizer of the Extracellular Vesicles and Infection meeting.

Our next Exosomes, Microvesicles and Infectious Disease meeting is scheduled for May 31, 2019 to June 1, 2019 at the Bolger Center in Potomac, Maryland.

Please use the link to Register: https://www.asemv.org/upcoming/

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