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.
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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.)
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Chemical References |
- Anti-HIV Agents
- H 0294
- Nuclear Proteins
- Pyrimidines
- alpha Karyopherins
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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
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