title: L74V increases the reverse transcriptase content of HIV-1 virions with non-nucleoside reverse transcriptase drug-resistant mutations L100I+K103N and K101E+G190S, which results in increased fitness.
abstract: The fitness of non-nucleoside reverse transcriptase inhibitor (NNRTI) drug-resistant reverse transcriptase (RT) mutants of HIV-1 correlates with the amount of RT in the virions and the RNase H activity of the RT. We wanted to understand the mechanism by which secondary NNRTI-resistance mutations, L100I and K101E, and the nucleoside resistance mutation, L74V, alter the fitness of K103N and G190S viruses. We measured the amount of RT in virions and the polymerization and RNase H activities of mutant RTs compared to wild-type, K103N and G190S. We found that L100I, K101E and L74V did not change the polymerization or RNase H activities of K103N or G190S RTs. However, L100I and K101E reduced the amount of RT in the virions and subsequent addition of L74V restored RT levels back to those of G190S or K103N alone. We conclude that fitness changes caused by L100I, K101E and L74V derive from their effects on RT content.
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Dongge
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bambara
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Dykes
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009705:Nucleosides / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016914:Ribonuclease H / Q000378:metabolism; D014771:Virion / Q000201:enzymology* / Q000502:physiology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D016914:Ribonuclease H
references.citation: J Virol. 1992 Nov;66(11):6547-54
references.pmid: 1404602
references.citation: J Infect Dis. 2006 Sep 15;194 Suppl 1:S51-8
references.pmid: 16921473
references.citation: J Virol. 1999 Oct;73(10):8448-56
references.pmid: 10482597
references.citation: J Mol Biol. 1998 Dec 11;284(4):1095-111
references.pmid: 9837729
references.citation: Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6125-9
references.pmid: 7687060
references.citation: Antivir Ther. 2010;15(4):641-50
references.pmid: 20587857
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):298-303
references.pmid: 12520007
references.citation: Virology. 1995 Oct 20;213(1):70-9
references.pmid: 7483281
references.citation: J Virol. 2010 Sep;84(18):9377-89
references.pmid: 20592075
references.citation: J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):405-11
references.pmid: 16763521
references.citation: Antimicrob Agents Chemother. 2000 Sep;44(9):2475-84
references.pmid: 10952598
references.citation: Antivir Ther. 2008;13(2):189-97
references.pmid: 18505170
references.citation: J Virol. 2001 Jul;75(14):6537-46
references.pmid: 11413321
references.citation: Protein Expr Purif. 2004 Mar;34(1):75-86
references.pmid: 14766302
references.citation: J Biol Chem. 2004 Jun 11;279(24):25489-96
references.pmid: 15044478
references.citation: Virology. 2006 Sep 15;353(1):184-92
references.pmid: 16797050
references.citation: Virology. 2010 Jul 5;402(2):228-37
references.pmid: 20399480
references.citation: J Virol. 2000 Sep;74(18):8390-401
references.pmid: 10954539
references.citation: Annu Rev Cell Biol. 1992;8:275-306
references.pmid: 1282352
references.citation: Antimicrob Agents Chemother. 1998 Feb;42(2):447-52
references.pmid: 9527805
references.citation: J Virol. 1999 Jul;73(7):5803-13
references.pmid: 10364332
references.citation: J Virol. 1996 Apr;70(4):2146-53
references.pmid: 8642636
references.citation: J Mol Biol. 1998 May 15;278(4):757-65
references.pmid: 9614940
references.citation: J Virol. 2001 Jun;75(11):4999-5008
references.pmid: 11333879
references.citation: J Acquir Immune Defic Syndr (1988). 1990;3(8):817-31
references.pmid: 1694894
references.citation: Virology. 2006 May 10;348(2):462-74
references.pmid: 16504235
references.citation: J Acquir Immune Defic Syndr (1988). 1992;5(7):647-57
references.pmid: 1377241
references.citation: J Virol. 2003 Jan;77(2):1512-23
references.pmid: 12502865
references.citation: Antiviral Res. 2009 Sep;83(3):317-23
references.pmid: 19555722