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 spliced retroviral mRNAs encoding capsid elements, requires a host cell protein termed "eukaryotic initiation factor 5A" (eIF-5A). This is the only protein containing hypusine, a lysine-derived hydroxylated residue that determines its proposed bioactivity, the translation of a subset of cellular mRNAs controlling G1-to-S transit of the cell cycle. We postulated that inhibiting the hypusine-forming deoxyhypusyl hydroxylase (DOHH) should, by depleting eukaryotic initiation factor 5A, compromise Rev function and thus reduce HIV-1 multiplication. We now report that the alpha-hydroxypyridones, specifically mimosine, a natural product, and deferiprone, an experimental drug, inhibited deoxyhypusyl hydroxylase in T-lymphocytic and promonocytic cell lines and, in a concentration-dependent manner, suppressed replication of HIV-1. However, the alpha-hydroxypyridones did not affect the formation of unspliced or multiply spliced HIV-1 transcripts. Rather, these agents caused Rev-dependent incompletely spliced HIV-1 mRNA such as gag, but not cellular "housekeeping" mRNAs, to disappear from polysomes. Consequently, alpha-hydroxypyridone-mediated depletion of eIF-5A decreased biosynthesis 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 incompletely spliced retroviral mRNAs, these compounds restrict HIV-1 to the early, nongenerative phase of its reproductive cycle. In the inducibly HIV-1 expressing T-cell line ACH-2, the deoxyhypusyl hydroxylase inhibitors triggered extensive apoptosis, particularly of cells that actively produce HIV-1. Selective suppression of retroviral protein biosynthesis and preferential apoptosis of retrovirally infected cells by alpha-hydroxypyridones point to a novel mode of antiretroviral action.
Andrus
L
L
The New York Blood Center, NY, USA.
Szabo
P
P
Grady
R W
RW
Hanauske
A R
AR
Huima-Byron
T
T
Slowinska
B
B
Zagulska
S
S
Hanauske-Abel
H M
HM
D019380:Anti-HIV Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D000077543:Deferiprone; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D008854:Microscopy, Electron; D008898:Mimosine / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*; D000097574:Eukaryotic Translation Initiation Factor 5A
D019380:Anti-HIV Agents; D000077543:Deferiprone; D004791:Enzyme Inhibitors; D016655:HIV Core Protein p24; D008239:Lysine; D008898:Mimosine; D006899:Mixed Function Oxygenases; D010448:Peptide Initiation Factors; D011728:Pyridones; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C047991:deoxyhypusine hydroxylase