title: Exploitation of the low fidelity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the nucleotide composition bias in the HIV-1 genome to alter the drug resistance development of HIV.
abstract: The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1) is significantly richer in adenine nucleotides than the statistically equal distribution of the four different nucleotides that is expected. This compositional bias may be due to the guanine-to-adenine (G-->A) nucleotide hypermutation of the HIV genome, which has been explained by dCTP pool imbalances during reverse transcription. The adenine nucleotide bias together with the poor fidelity of HIV-1 reverse transcriptase markedly enhances the genetic variation of HIV and may be responsible for the rapid emergence of drug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering the endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these antimetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (G-->A) to an adenine-to-guanine (A-->G) nucleotide pattern in the intact HIV-1-infected lymphocyte cultures. Forcing the virus to change its inherent nucleotide bias may lead to better control of viral drug resistance development.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: A
authors.initials: A
authors.lastname: San-Félix
authors.forename: S
authors.initials: S
authors.lastname: Velázquez
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J N
authors.initials: JN
authors.lastname: Anderson
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D004352:Drug Resistance, Microbial; D016679:Genome, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D000963:Antimetabolites; D003845:Deoxycytosine Nucleotides; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D013942:Thymine Nucleotides; C082493:1-(2',5'-bis-O-(tert-butyldimethylsilylribofuranosyl)-3-N-methylthymine)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide); C024107:2'-deoxycytidine 5'-triphosphate; D054303:HIV Reverse Transcriptase; C024157:thymidine 5'-triphosphate; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine