Mechanism of the potentiating effect of ribavirin on the activity of 2',3'-dideoxyinosine against human immunodeficiency virus.
Ribavirin enhances the anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine (ddIno) in MT-4, CEM and peripheral blood lymphocyte cells. Ribavirin causes an increase in the levels of IMP, the presumed phosphate donor for the conversion of ddIno to ddIMP by 5'-nucleotidase. Consequently, ribavirin stimulates the conversion of ddIno to its antivirally active metabolite ddATP. Ribavirin also causes a marked depletion of the guanine nucleotide pools. The increase in IMP pool levels may result from (i) a direct inhibitory effect of ribavirin 5'-monophosphate on IMP dehydrogenase (which converts IMP to XMP) and (ii) an indirect inhibition of adenylosuccinate synthetase by the decreased GTP and dGTP pools (since GTP is an obligatory cofactor in the conversion of IMP to succinyl AMP). GTP depletion plays a key role in the accumulation of IMP and the resultant higher rate of ddIno phosphorylation to ddIMP and eventually ddATP. Our findings are in agreement with the observations that guanosine and 2'-deoxyguanosine, but not 2'-deoxyadenosine, reverse (i) the stimulatory effect of ribavirin on the anti-human immunodeficiency virus activity of ddIno and (ii) the accumulation of endogenous IMP pools as well as accumulation of [3H]IMP from exogenous [3H]hypoxanthine in ribavirin-treated cells.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
J
J
Balzarini
C K
CK
Lee
P
P
Herdewijn
E
E
De Clercq
D001711:Biotransformation; D002460:Cell Line; D016049:Didanosine / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D015726:Giant Cells / Q000187:drug effects; D006150:Guanine Nucleotides / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D007291:Inosine Monophosphate / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D012254:Ribavirin / Q000378:metabolism / Q000494:pharmacology*
D006150:Guanine Nucleotides; D007042:Hypoxanthines; D007291:Inosine Monophosphate; D019271:Hypoxanthine; D012254:Ribavirin; D016049:Didanosine