This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haffar, O. K.
Right arrow Articles by Bukrinsky, M. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haffar, O. K.
Right arrow Articles by Bukrinsky, M. I.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 1998, p. 1133-1138, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

CNI-H0294, a Nuclear Importation Inhibitor of the Human Immunodeficiency Virus Type 1 Genome, Abrogates Virus Replication in Infected Activated Peripheral Blood Mononuclear Cells

Omar K. Haffar,1,* Molly D. Smithgall,1 Serguei Popov,2 Peter Ulrich,2 A. Gregory Bruce,1 Steven G. Nadler,1 Anthony Cerami,2 and Michael I. Bukrinsky2

Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121,1 and The Picower Institute for Medical Research, Manhasset, New York 110302

Received 26 September 1997/Returned for modification 18 December 1997/Accepted 9 February 1998

Active nuclear importation of the human immunodeficiency virus (HIV) type 1 (HIV-1) preintegration complex (PIC) is required for the productive infection of nondividing cells, but it is believed to be dispensable for the infection of proliferating cells, such as activated T lymphocytes. To investigate this question, we exploited the properties of the small arylene bis (methyl ketone) compound CNI-H0294. We have previously shown that this compound associated with the HIV-1 matrix protein nuclear localization sequence and blocked binding of the HIV-1 PIC to yeast karyopherin alpha . CNI-H0294 abrogated nuclear importation of the HIV-1 genome in macrophages and effectively inhibited infection of nondividing cells. In this study we demonstrate that CNI-H0294 inhibits binding of the HIV-1 PIC to human karyopherin alpha  and reduces nuclear importation of the viral genome in primary peripheral blood mononuclear cells (PBMCs). We also demonstrate that CNI-H0294 inhibits acute infection of PBMC cultures in vitro with a primary isolate of HIV-1 and reduces virus replication and virus load in cultures of endogenously infected PBMCs from seropositive individuals. Thus, as for infection of nondividing, terminally differentiated macrophages, HIV-1 uses active nuclear importation of the virus genome to infect activated CD4+ T cells. These results support nuclear importation as a novel target and CNI-H0294 and its derivatives as novel compounds for therapeutic intervention in HIV infection and AIDS.

* Corresponding author. Present address: Cytokine Networks Inc., 101 Elliot Ave. West, Suite 428, Seattle, WA 98119. Phone: (206) 283-0236. Fax: (206) 270-3300. E-mail: okhaffar{at}wolfenet.com.

Antimicrobial Agents and Chemotherapy, May 1998, p. 1133-1138, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Haffar, O., Dubrovsky, L., Lowe, R., Berro, R., Kashanchi, F., Godden, J., Vanpouille, C., Bajorath, J., Bukrinsky, M. (2005). Oxadiazols: a New Class of Rationally Designed Anti-Human Immunodeficiency Virus Compounds Targeting the Nuclear Localization Signal of the Viral Matrix Protein. J. Virol. 79: 13028-13036 [Abstract] [Full Text]  
  • Iordanskiy, S., Zhao, Y., DiMarzio, P., Agostini, I., Dubrovsky, L., Bukrinsky, M. (2004). Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood 104: 1867-1872 [Abstract] [Full Text]  
  • Bahr, G. M., Darcissac, E. C. A., Casteran, N., Amiel, C., Cocude, C., Truong, M.-J., Dewulf, J., Capron, A., Mouton, Y. (2001). Selective Regulation of Human Immunodeficiency Virus-Infected CD4+ Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice. J. Virol. 75: 6941-6952 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»