CNI-H0294, A NUCLEAR IMPORTATION INHIBITOR OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GENOME, ABROGATES VIRUS-REPLICATION IN INFECTED ACTIVATED PERIPHERAL-BLOOD MONONUCLEAR-CELLS

Active nuclear importation of the human immunodeficiency virus (HIV) t ype 1 (HIV-1) preintegration complex (PIC) is required for the product ive infection of nondividing cells, but it is believed to be dispensab le for the infection of proliferating cells, such as activated T lymph ocytes. To investigate this question, we exploited the properties of t he small arylene bis (methyl ketone) compound CNI-H0294. We have previ ously shown that this compound associated with the HIV-1 matrix protei n nuclear localization sequence and blocked binding of the HIV-1 PIC t o 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 inhibi ts binding of the HIV-1 PIC to human karyopherin a and reduces nuclear importation of the viral genome in primary peripheral blood mononucle ar cells (PBMCs). We also demonstrate that CNI-H0294 inhibits acute in fection of PBMC cultures in vitro with a primary isolate of HIV-1 and reduces virus replication and virus load in cultures of endogenously i nfected 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 inte rvention in HIV infection and AIDS.