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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.


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