Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form
D-Scholarship @ Pitt Banner and Links to Homepage

Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase

Brehm, JH and Scott, Y and Koontz, DL and Perry, S and Hammer, S and Katzenstein, D and Mellors, JW and Sluis-Cremer, N (2012) Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase. PLoS ONE, 7 (2).

[img]
Preview
 PDF
Published Version
Available under License : See the attached license file.
Download (212kB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.
Download (1kB)

Abstract

Background: We previously demonstrated in vitro that zidovudine (AZT) selects for A371V in the connection domain and Q509L in ribonuclease H (RNase H) domain of HIV-1 reverse transcriptase (RT) which, together with the thymidine analog mutations D67N, K70R and T215F, confer greater than 100-fold AZT resistance. The goal of the current study was to determine whether AZT monotherapy in HIV-1 infected patients also selects the A371V, Q509L or other mutations in the C-terminal domains of HIV-1 RT. Methodology/Principal Findings: Full-length RT sequences in plasma obtained pre- and post-therapy were compared in 23 participants who received AZT monotherapy from the AIDS Clinical Trials Group study 175. Five of the 23 participants reached a primary study endpoint. Mutations significantly associated with AZT monotherapy included K70R (p = 0.003) and T215Y (p = 0.013) in the polymerase domain of HIV-1 RT, and A360V (p = 0.041) in the connection domain of HIV-1 RT. HIV-1 drug susceptibility assays demonstrated that A360V, either alone or in combination with thymidine analog mutations, decreased AZT susceptibility in recombinant viruses containing participant-derived full-length RT sequences or site-directed mutant RT. Biochemical studies revealed that A360V enhances the AZT-monophosphate excision activity of purified RT by significantly decreasing the frequency of secondary RNase H cleavage events that reduce the RNA/DNA duplex length and promote template/primer dissociation. Conclusions: The A360V mutation in the connection domain of RT was selected in HIV-infected individuals that received AZT monotherapy and contributed to AZT resistance. © 2012 Brehm et al.

Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brehm, JH
Scott, Yyas23@pitt.eduYAS23
Koontz, DLzonarich@pitt.eduZONARICH
Perry, S
Hammer, S
Katzenstein, D
Mellors, JWjwm1@pitt.eduJWM1
Sluis-Cremer, Nnps2@pitt.eduNPS2
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
InvestigatorCrumpacker, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCraven, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorChapman, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGrodman, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorChance, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCitraro, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDavidson, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHirschtick, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPottage, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPulvirenti, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBalfour, HUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorReed, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSwindells, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorNelson, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMildvan, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHassett, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSimpson, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLuyks, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRichman, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSpector, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJacobsen, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorTallman, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRinki, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCarroll, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorVan Raalte, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMitsuyasu, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBeall, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHardy, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMathisen, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCollier, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRoyer, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorParadise, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSacks, LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPowderly, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSlack, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorStiffler, TUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRoyal, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPara, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorStark, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJackson, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorNeidig, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorEron, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLane, TUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHorton, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRagan, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorAbrams, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJohnson, LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDybek, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCarroll, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorReichman, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGreisberger, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHewitt, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBlair, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFife, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGoldman, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorTodd, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorZwickl, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKuritzkes, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorWaite, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRay, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHyslop, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMushatt, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorClark, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorZachary, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorWong, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBrinkdopke, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJackson, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDayton, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSoeiro, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorStein, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSchliosberg, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorZingman, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSteigbigel, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFuhrer, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMariuz, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorWallace, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGeiseler, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLeedom, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCordina, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorOlson, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFischl, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJayaweera, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorReese, J PatroneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDale, EUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSepkowitz, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSharp, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorShepp, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBartlett, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBecker, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBaker, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorWright, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorEhmann, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorZurlo, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKreher, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDamianos, FUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCheeseman, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorAvato, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBova, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSands, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGrieco, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMcKinley, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRivera, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorO'Connor, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDavis, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSquires, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGnann, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSaag, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPollard, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBorucki, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorWaterman, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCasey, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFrank, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDunbar, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMatozzo, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHauptman, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMcAuliffe, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRosenwald, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorValentine, FUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKloser, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCorrell, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBartlett, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDodge, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRobinson, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorShipp, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFriedland, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCooney, EUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFiellin, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGriffith, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorVazquez, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCruz-Ortiz, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRamirez, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLopez, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGreaves, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMcNeil, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDelapenha, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHolley-Trimmer, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHeath-Chiozzi, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorOgata-Arakaki, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorAkina, S BonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMillard, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPierce, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKumar, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorTimpone, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGreen, LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMcIntosh, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRubin-Hale, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKnox-Burke, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMahoney-West, HUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFutterman, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMonte, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHoffman, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorChirgwin, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSmith, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGarner, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHauck, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorVan Dyke, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorAbdalian, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDegenstein, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPrice, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorBrettler, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRickles, FUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSmith, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCornell, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSeremetis, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLipton, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCisar, LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorArkin, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRagni, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSteinberg, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLessinger, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHanna, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHadley, TUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPenner, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorAdair, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCzapek, EUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRitter, HUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorHoots, WUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCantini, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRutherford, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMacFarlane, DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorStuart, RUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorStabler, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGiambartolomei, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFord, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGjerset, GUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGoldsmith, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSosa, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorSanders, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorKasdan, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCook, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLandry, BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorNerhood, LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorColon-Ruiz, MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorOjudun, KUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMartinez, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPettinelli, CUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 21 February 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0031558
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
School of Medicine > Infectious Diseases and Microbiology
Refereed: Yes
MeSH Headings: Adenosine Triphosphate--pharmacology; Amino Acid Substitution--genetics; Anti-HIV Agents--pharmacology; Anti-HIV Agents--therapeutic use; Drug Resistance, Viral--drug effects; Drug Resistance, Viral--genetics; HIV Infections--blood; HIV Infections--drug therapy; HIV Infections--virology; HIV Reverse Transcriptase--chemistry; HIV Reverse Transcriptase--genetics; HIV-1--drug effects; HIV-1--enzymology; HIV-1--genetics; Humans; Mutagenesis, Site-Directed; Mutant Proteins--metabolism; Mutation--genetics; Phenotype; Protein Structure, Tertiary; RNA, Viral--blood; Recombination, Genetic--genetics; Ribonuclease H--metabolism; Zidovudine--pharmacology; Zidovudine--therapeutic use
Other ID: NLM PMC3283647
PubMed Central ID: PMC3283647
PubMed ID: 22363673
Date Deposited: 13 Sep 2012 18:03
Last Modified: 21 Jan 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/14142

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com

Actions (login required)

View Item View Item