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4. The identification of unique serum proteins of HIV-1 latently infected long-term non-progressor patients

Author

Van Duyne Rachel, Guendel Irene, Kehn-Hall Kylene, Easley Rebecca, Klase Zachary, Liu Chenglong, Young Mary, and Kashanchi Fatah

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The search for disease biomarkers within human peripheral fluids has become a favorable approach to preventative therapeutics throughout the past few years. The comparison of normal versus disease states can identify an overexpression or a suppression of critical proteins where illness has directly altered a patient's cellular homeostasis. In particular, the analysis of HIV-1 infected serum is an attractive medium with which to identify altered protein expression due to the ease and non-invasive methods of collecting samples as well as the corresponding insight into the in vivo interaction of the virus with infected cells/tissue. The utilization of proteomic techniques to globally identify differentially expressed serum proteins in response to HIV-1 infection is a significant undertaking that is complicated due to the innate protein profile of human serum. Results Here, the depletion of 12 of the most abundant serum proteins, followed by two-dimensional gel electrophoresis coupled with identification of these proteins using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, has allowed for the identification of differentially expressed, low abundant serum proteins. We have analyzed and compared serum samples from HIV-1 infected subjects who are being treated using highly active antiretroviral therapy (HAART) to those who are latently infected but have not progressed to AIDS despite the absence of treatment, i.e. long term non-progressors (LTNPs). Here we have identified unique serum proteins that are differentially expressed in LTNP HIV-1 patients and may contribute to the ability of these patients to combat HIV-1 infection in the absence of HAART. We focused on the cdk4/6 cell cycle inhibitor p16INK4A and found that the treatment of HIV-1 latently infected cell lines with p16INK4A decreases viral production despite it not being expressed endogenously in these cells. Conclusions Identification of these unique proteins may serve as an indication of altered viral states in response to infection as well as a natural phenotypic variability in response to HIV-1 infection in a given population.

Published
2010
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5. Inhibition of human immunodeficiency virus type-1 by cdk inhibitors

Author

Kehn-Hall Kylene, Agbottah Emmanuel T, Guendel Irene, and Kashanchi Fatah

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Current therapy for human immunodeficiency virus (HIV-1) infection relies primarily on the administration of anti-retroviral nucleoside analogues, either alone or in combination with HIV-protease inhibitors. Although these drugs have a clinical benefit, continuous therapy with the drugs leads to drug-resistant strains of the virus. Recently, significant progress has been made towards the development of natural and synthetic agents that can directly inhibit HIV-1 replication or its essential enzymes. We previously reported on the pharmacological cyclin-dependent kinase inhibitor (PCI) r-roscovitine as a potential inhibitor of HIV-1 replication. PCIs are among the most promising novel antiviral agents to emerge over the past few years. Potent activity on viral replication combined with proliferation inhibition without the emergence of resistant viruses, which are normally observed in HAART patients; make PCIs ideal candidates for HIV-1 inhibition. To this end we evaluated twenty four cdk inhibitors for their effect on HIV-1 replication in vitro. Screening of these compounds identified alsterpaullone as the most potent inhibitor of HIV-1 with activity at 150 nM. We found that alsterpaullone effectively inhibits cdk2 activity in HIV-1 infected cells with a low IC50 compared to control uninfected cells. The effects of alsterpaullone were associated with suppression of cdk2 and cyclin expression. Combining both alsterpaullone and r-roscovitine (cyc202) in treatment exhibited even stronger inhibitory activities in HIV-1 infected PBMCs.

Published
2010
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6. The utilization of humanized mouse models for the study of human retroviral infections

Author

Saifuddin Mohammed, Kehn-Hall Kylene, Carpio Lawrence, Guendel Irene, Pedati Caitlin, Van Duyne Rachel, and Kashanchi Fatah

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract The development of novel techniques and systems to study human infectious diseases in both an in vitro and in vivo settings is always in high demand. Ideally, small animal models are the most efficient method of studying human afflictions. This is especially evident in the study of the human retroviruses, HIV-1 and HTLV-1, in that current simian animal models, though robust, are often expensive and difficult to maintain. Over the past two decades, the construction of humanized animal models through the transplantation and engraftment of human tissues or progenitor cells into immunocompromised mouse strains has allowed for the development of a reconstituted human tissue scaffold in a small animal system. The utilization of small animal models for retroviral studies required expansion of the early CB-17 scid/scid mouse resulting in animals demonstrating improved engraftment efficiency and infectivity. The implantation of uneducated human immune cells and associated tissue provided the basis for the SCID-hu Thy/Liv and hu-PBL-SCID models. Engraftment efficiency of these tissues was further improved through the integration of the non-obese diabetic (NOD) mutation leading to the creation of NODSCID, NOD/Shi-scid IL2rγ-/-, and NOD/SCID β2-microglobulinnull animals. Further efforts at minimizing the response of the innate murine immune system produced the Rag2-/-γc-/- model which marked an important advancement in the use of human CD34+ hematopoietic stem cells. Together, these animal models have revolutionized the investigation of retroviral infections in vivo.

Published
2009
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7. 9-aminoacridine Inhibition of HIV-1 Tat Dependent Transcription

Author

Kashanchi Fatah, Dowd Cynthia, Agbottah Emmanuel, Coley William, Van Duyne Rachel, Easley Rebecca, Carpio Lawrence, Guendel Irene, and Kehn-Hall Kylene

Subjects
Infectious and parasitic diseases, RC109-216
Abstract

Abstract As part of a continued search for more efficient anti-HIV-1 drugs, we are focusing on the possibility that small molecules could efficiently inhibit HIV-1 replication through the restoration of p53 and p21WAF1 functions, which are inactivated by HIV-1 infection. Here we describe the molecular mechanism of 9-aminoacridine (9AA) mediated HIV-1 inhibition. 9AA treatment resulted in inhibition of HIV LTR transcription in a specific manner that was highly dependent on the presence and location of the amino moiety. Importantly, virus replication was found to be inhibited in HIV-1 infected cell lines by 9AA in a dose-dependent manner without inhibiting cellular proliferation or inducing cell death. 9AA inhibited viral replication in both p53 wildtype and p53 mutant cells, indicating that there is another p53 independent factor that was critical for HIV inhibition. p21WAF1 is an ideal candidate as p21WAF1 levels were increased in both p53 wildtype and p53 mutant cells, and p21WAF1 was found to be phosphorylated at S146, an event previously shown to increase its stability. Furthermore, we observed p21WAF1 in complex with cyclin T1 and cdk9 in vitro, suggesting a direct role of p21WAF1 in HIV transcription inhibition. Finally, 9AA treatment resulted in loss of cdk9 from the viral promoter, providing one possible mechanism of transcriptional inhibition. Thus, 9AA treatment was highly efficient at reactivating the p53 – p21WAF1 pathway and consequently inhibiting HIV replication and transcription.

Published
2009
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8. Melioidosis after Hurricanes Irma and Maria, St. Thomas/St. John District, US Virgin Islands, October 2017

Author

Guendel, Irene, Ekpo, Lisa LaPlace, Hinkle, Mary K., Harrison, Cosme J., Blaney, David D., Gee, Jay E., Elrod, Mindy G., Boyd, Sandra, Gulvik, Christopher A., Liu, Lindy, Hoffmaster, Alex R., Ellis, Brett R., Hunte-Ceasar, Tai, and Ellis, Esther M.

Subjects
United States. Centers for Disease Control and Prevention, Pseudomonas infections -- Care and treatment -- Diagnosis -- Health aspects, Tetracyclines -- Health aspects, Imipenem -- Health aspects, Infection -- Care and treatment -- Diagnosis -- Health aspects, Hurricanes -- Health aspects, Methicillin -- Health aspects, Meropenem -- Health aspects, Diabetics -- Care and treatment -- Health aspects, Septicemia, Health
Abstract

Melioidosis is caused by Burkholderia pseudomallei, a saprophytic, gram-negative bacillus endemic to tropical regions worldwide (1). Diagnosis is difficult because of wide-ranging clinical manifestations (2), and this bacterium is innately [...]

Published
2019
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11. Burkholderia pseudomallei in Soil, US Virgin Islands, 2019

Author

Stone, Nathan E., Hall, Carina M., Browne, A. Springer, Sahl, Jason W., Hutton, Shelby M., Santana-Propper, Ella, Celona, Kimberly R., Guendel, Irene, Harrison, Cosme J., Gee, Jay E., Elrod, Mindy G., Busch, Joseph D., Hoffmaster, Alex R., Ellis, Esther M., and Wagner, David M.

Subjects
Pseudomonas infections -- Risk factors, Burkholderia pseudomallei -- Distribution -- Environmental aspects, Soil microbiology -- Research, Microbiological research, Company distribution practices, Health
Abstract

Burkholderia pseudomallei is a gram-negative soil-dwelling bacterium and the causative agent of melioidosis (1). B. pseudomallei is endemic to tropical regions around the world (1), but its environmental distribution in [...]

Published
2020
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13. Spatial, Sociodemographic, and Weather Analysis of the Zika Virus Outbreak: U.S. Virgin Islands, January 2016–January 2018

Author

Browne, A. Springer, primary, Rickless, David, additional, Hranac, Carter Reed, additional, Beron, Andrew, additional, Hillman, Breanna, additional, de Wilde, Leah, additional, Short, Harris, additional, Harrison, Cosme, additional, Prosper, Andra, additional, Joseph, E. Joy, additional, Guendel, Irene, additional, Ekpo, Lisa L., additional, Roth, Joseph, additional, Grossman, Marissa, additional, Ellis, Brett R., additional, and Ellis, Esther M., additional

Published
2022
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15. Determination of freedom-from-rabies for small Indian mongoose populations in the United States Virgin Islands, 2019–2020

Author

Browne, A. Springer, primary, Cranford, Hannah M., additional, Morgan, Clint N., additional, Ellison, James A., additional, Berentsen, Are, additional, Wiese, Nicholas, additional, Medley, Alexandra, additional, Rossow, John, additional, Jankelunas, Leanne, additional, McKinley, Alan S., additional, Lombard, Claudia D., additional, Angeli, Nicole F., additional, Kelley, Thomas, additional, Valiulus, Jennifer, additional, Bradford, Bethany, additional, Burke-France, Valicia J., additional, Harrison, Cosme J., additional, Guendel, Irene, additional, Taylor, Marissa, additional, Blanchard, Gerard L., additional, Doty, Jeffrey B., additional, Worthington, David J., additional, Horner, David, additional, Garcia, Keith R., additional, Roth, Joseph, additional, Ellis, Brett R., additional, Bisgard, Kristine M., additional, Wallace, Ryan, additional, and Ellis, Esther M., additional

Published
2021
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16. First Reported Human Cases of Leptospirosis in the United States Virgin Islands in the Aftermath of Hurricanes Irma and Maria, September–November 2017

Author

Marinova-Petkova, Atanaska, primary, Guendel, Irene, additional, Strysko, Jonathan P, additional, Ekpo, Lisa LaPlace, additional, Galloway, Renee, additional, Yoder, Jonathan, additional, Kahler, Amy, additional, Artus, Aileen, additional, Hoffmaster, Alex R, additional, Bower, William A, additional, Walke, Henry, additional, Ellis, Brett R, additional, Hunte-Ceasar, Tai, additional, Ellis, Esther M, additional, and Schafer, Ilana J, additional

Published
2019
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19. microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection

Author

Carpio, Lawrence, Klase, Zachary, Coley, William, Guendel, Irene, Choi, Sarah, Van Duyne, Rachel, Narayanan, Aarthi, Kehn-Hall, Kylene, Meijer, Laurent, and Kashanchi, Fatah

Subjects
microRNA, ATP analogs, viruses, HIV-1, TAR, Tat transactivation, cdk inhibitor, Research Article
Abstract

RNA interference plays a significant role in manipulating cellular and viral mechanisms to maintain latency during HIV-1 infection. HIV-1 produces several microRNAs including one from the TAR element which alter the host's response to infection. Since cyclin/cdk complexes are important for viral transcription, these studies focus on the possible cdk inhibitors that inhibit viral transcription, without affecting normal cellular mechanisms. Roscovitine and Flavopiridol are well-studied cdk inhibitors that are effective at suppressing their target cdks at a low IC50. These cdk inhibitors and possibly future generations of drugs are affected by microRNA mechanisms. From our studies, we developed a third generation derivative called CR8#13. In cells that lack Dicer there was a higher level of basal viral LTR-reporter transcription. When drugs, specifically Flavopiridol and CR8#13 were added, the transcriptional inhibition of the LTR was less potent in cells that lacked Dicer. Also, after transfection with HIV-1 clone (pNL4.3), CR8 and CR8#13 derivatives were shown to be more effective viral transcription inhibitors in cell lines that contained Dicer (T-cells) as compared to Dicer deficient lines (monocytes). We next asked whether the addition of CR8 or CR8#13 could possibly increase levels of TAR microRNA in HIV-1 LTR containing cells. We demonstrate that the 3'TAR microRNA is produced in higher amounts after drug treatment, resulting in microRNA recruitment to the LTR. MicroRNA recruitment results in chromatin alteration, changes in Pol II phosphorylation and viral transcription inhibition. In conclusion, our results indicate that viral microRNA, specifically the TAR microRNA produced from the HIV-1 LTR is responsible for maintaining latent infections by manipulating host cell mechanisms to limit transcription from the viral LTR promoter. With the microRNA machinery present, cdk inhibitors are able to significantly increase the amount of TAR microRNA, leading to downregulation of viral LTR transcription.

Published
2010

20. Notes from the Field: Epidemic Keratoconjunctivitis Outbreak Associated with Human Adenovirus Type 8 — U.S. Virgin Islands, June–November 2016

Author

Killerby,, Marie E., primary, Stuckey,, Matthew J., additional, Guendel,, Irene, additional, Sakthivel,, Senthilkumar, additional, Lu,, Xiaoyan, additional, Erdman,, Dean D., additional, Schneider,, Eileen, additional, Fagan,, Ryan, additional, Davis,, Michelle S., additional, Watson,, John T., additional, Gerber,, Susan I., additional, Biggs,, Holly M., additional, and Ellis,, Esther M., additional

Published
2017
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23. Curcumin inhibits Rift Valley fever virus replication in human cells.

Author

Narayanan, Aarthi, primary, Kehn-Hall, Kylene, additional, Senina, Svetlana, additional, Lundberg, Lindsay, additional, Van Duyne, Rachel, additional, Guendel, Irene, additional, Das, Ravi, additional, Baer, Alan, additional, Bethel, Laura, additional, Turell, Michael, additional, Hartman, Amy Lynn, additional, Das, Bhaskar, additional, Bailey, Charles, additional, and Kashanchi, Fatah, additional

Published
2014
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24. Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication

Author

Guendel, Irene, primary, Iordanskiy, Sergey, additional, Van Duyne, Rachel, additional, Kehn-Hall, Kylene, additional, Saifuddin, Mohammed, additional, Das, Ravi, additional, Jaworski, Elizabeth, additional, Sampey, Gavin C., additional, Senina, Svetlana, additional, Shultz, Leonard, additional, Narayanan, Aarthi, additional, Chen, Hao, additional, Lepene, Benjamin, additional, Zeng, Chen, additional, and Kashanchi, Fatah, additional

Published
2014
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26. Exosomes derived from HTLV-1 infected cells contain the viral protein Tax

Author

Narayanan, Aarthi, primary, Jaworski, Elizabeth, additional, Van Duyne, Rachel, additional, Iordanskiy, Sergey, additional, Guendel, Irene, additional, Das, Ravi, additional, Currer, Robert, additional, Sampey, Gavin, additional, Chung, Myung, additional, Kehn-Hall, Kylene, additional, Bailey, Charles, additional, Popratiloff, Anastas, additional, and Kashanchi, Fatah, additional

Published
2014
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28. Exosomes Derived from HIV-1-infected Cells Contain Trans-activation Response Element RNA

Author

Narayanan, Aarthi, primary, Iordanskiy, Sergey, additional, Das, Ravi, additional, Van Duyne, Rachel, additional, Santos, Steven, additional, Jaworski, Elizabeth, additional, Guendel, Irene, additional, Sampey, Gavin, additional, Dalby, Elizabeth, additional, Iglesias-Ussel, Maria, additional, Popratiloff, Anastas, additional, Hakami, Ramin, additional, Kehn-Hall, Kylene, additional, Young, Mary, additional, Subra, Caroline, additional, Gilbert, Caroline, additional, Bailey, Charles, additional, Romerio, Fabio, additional, and Kashanchi, Fatah, additional

Published
2013
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29. Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription

Author

Van Duyne, Rachel, primary, Guendel, Irene, additional, Jaworski, Elizabeth, additional, Sampey, Gavin, additional, Klase, Zachary, additional, Chen, Hao, additional, Zeng, Chen, additional, Kovalskyy, Dmytro, additional, el Kouni, Mahmoud H., additional, Lepene, Benjamin, additional, Patanarut, Alexis, additional, Nekhai, Sergei, additional, Price, David H., additional, and Kashanchi, Fatah, additional

Published
2013
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30. Use of ATP analogs to inhibit HIV-1 transcription

Author

Narayanan, Aarthi, primary, Sampey, Gavin, additional, Van Duyne, Rachel, additional, Guendel, Irene, additional, Kehn-Hall, Kylene, additional, Roman, Jessica, additional, Currer, Robert, additional, Galons, Hervé, additional, Oumata, Nassima, additional, Joseph, Benoît, additional, Meijer, Laurent, additional, Caputi, Massimo, additional, Nekhai, Sergei, additional, and Kashanchi, Fatah, additional

Published
2012
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31. Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

Author

Narayanan, Aarthi, primary, Kehn-Hall, Kylene, additional, Senina, Svetlana, additional, Lundberg, Lindsay, additional, Van Duyne, Rachel, additional, Guendel, Irene, additional, Das, Ravi, additional, Baer, Alan, additional, Bethel, Laura, additional, Turell, Michael, additional, Hartman, Amy Lynn, additional, Das, Bhaskar, additional, Bailey, Charles, additional, and Kashanchi, Fatah, additional

Published
2012
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34. Modulation of GSK-3β Activity in Venezuelan Equine Encephalitis Virus Infection

Author

Kehn-Hall, Kylene, primary, Narayanan, Aarthi, additional, Lundberg, Lindsay, additional, Sampey, Gavin, additional, Pinkham, Chelsea, additional, Guendel, Irene, additional, Van Duyne, Rachel, additional, Senina, Svetlana, additional, Schultz, Kimberly L., additional, Stavale, Eric, additional, Aman, M. Javad, additional, Bailey, Charles, additional, and Kashanchi, Fatah, additional

Published
2012
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37. Varying Modulation of HIV-1 LTR Activity by BAF Complexes

Author

Van Duyne, Rachel, primary, Guendel, Irene, additional, Narayanan, Aarthi, additional, Gregg, Edward, additional, Shafagati, Nazly, additional, Tyagi, Mudit, additional, Easley, Rebecca, additional, Klase, Zachary, additional, Nekhai, Sergei, additional, Kehn-Hall, Kylene, additional, and Kashanchi, Fatah, additional

Published
2011
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43. Absence of DICER in Monocytes and Its Regulation by HIV-1

Author

Coley, William, primary, Van Duyne, Rachel, additional, Carpio, Lawrence, additional, Guendel, Irene, additional, Kehn-Hall, Kylene, additional, Chevalier, Sebastien, additional, Narayanan, Aarthi, additional, Luu, Truong, additional, Lee, Norman, additional, Klase, Zachary, additional, and Kashanchi, Fatah, additional

Published
2010
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