title: 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.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA. okhaffar@wolfenet.com
authors.forename: O K
authors.initials: OK
authors.lastname: Haffar
authors.forename: M D
authors.initials: MD
authors.lastname: Smithgall
authors.forename: S
authors.initials: S
authors.lastname: Popov
authors.forename: P
authors.initials: P
authors.lastname: Ulrich
authors.forename: A G
authors.initials: AG
authors.lastname: Bruce
authors.forename: S G
authors.initials: SG
authors.lastname: Nadler
authors.forename: A
authors.initials: A
authors.lastname: Cerami
authors.forename: M I
authors.initials: MI
authors.lastname: Bukrinsky
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000821:virology; D006679:HIV Seropositivity / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000821:virology; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*; D028901:alpha Karyopherins
chemical_list: D019380:Anti-HIV Agents; C097286:H 0294; D009687:Nuclear Proteins; D011743:Pyrimidines; D028901:alpha Karyopherins