ANTIRETROVIRAL EFFECTS OF DEOXYHYPUSYL HYDROXYLASE INHIBITORS - A HYPUSINE-DEPENDENT HOST-CELL MECHANISM FOR REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1)

The HIV-1 protein Rev, critical for translation of incompletely splice d retroviral mRNAs encoding capsid elements, requires a host cell prot ein termed ''eukaryotic initiation factor 5A'' (eIF-5A). This is the o nly protein containing hypusine, a lysine derived hydroxylated residue that determines its proposed bioactivity, the translation of a subset of cellular mRNAs controlling G(1)-to-S transit of the cell cycle. We postulated that inhibiting the hypusine-forming deoxyhypusyl hydroxyl ase (DOHH) should, by depleting eukaryotic initiation factor 5A, compr omise Rev function and thus reduce HIV-1 multiplication. We now report that the alpha-hydroxypyridones, specifically mimosine, a natural pro duct, and deferiprone, an experimental drug, inhibited deoxyhypusyl hy droxylase in T-lymphocytic and promonocytic cell lines and, in a conce ntration-dependent manner, suppressed replication of HIV-1. However, t he alpha-hydroxypyridones did not affect the formation of unspliced or multiply spliced HIV-1 transcripts. Rather, these agents caused Rev d ependent incompletely spliced HIV-1 mRNA such as gag, but not cellular ''housekeeping'' mRNAs, to disappear from polysomes. Consequently, al pha-hydroxypyridone-mediated depletion of eIF-5A decreased biosynthesi s of structural HIV-1 protein encoded by gag, measured as p24, whereas the induced formation of cellular protein like tumor necrosis factor alpha remained unaffected. By interfering with the translation of inco mpletely spliced retroviral mRNAs, these compounds restrict HIV-1 to t he early, nongenerative phase of its reproductive cycle. In the induci bly HIV-1 expressing T-cell line ACH-2, the deoxyhypusyl hydroxylase i nhibitors triggered extensive apoptosis, particularly of cells that ac tively produce HIV-1. Selective suppression of retroviral protein bios ynthesis and preferential apoptosis of retrovirally infected cells by alpha-hydroxypyridones point to a novel mode of antiretroviral action. (C) 1998 Elsevier Science Inc.