CNI-H0294, a nuclear importation inhibitor of the human immunodeficiency virus type 1 genome, abrogates virus replication in infected activated peripheral blood mononuclear cells.

Abstract

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.

• Authors: O K Haffar, M D Smithgall, S Popov, P Ulrich, A G Bruce, S G Nadler, A Cerami, M I Bukrinsky
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 42 Issue 5 Pg. 1133-8 (May 1998) ISSN: 0066-4804 [Print] United States
• PMID: 9593140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• H 0294
• Nuclear Proteins
• Pyrimidines
• alpha Karyopherins

Topics

• Anti-HIV Agents (pharmacology)
• Binding Sites (drug effects)
• Cells, Cultured (drug effects, virology)
• HIV Seropositivity (virology)
• HIV-1 (drug effects, growth & development, metabolism)
• Humans
• Leukocytes, Mononuclear (drug effects, virology)
• Nuclear Proteins (drug effects, metabolism)
• Pyrimidines (pharmacology)
• T-Lymphocytes (drug effects, physiology)
• Virus Replication (drug effects)
• alpha Karyopherins