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Mutations that abrogate human immunodeficiency virus type 1 reverse transcriptase dimerization affect maturation of the reverse transcriptase heterodimer

Wapling, Johanna, Moore, Katie L., Sonza, Secondo, Mak, Johnson and Tachedjian, Gilda 2005, Mutations that abrogate human immunodeficiency virus type 1 reverse transcriptase dimerization affect maturation of the reverse transcriptase heterodimer, Journal of virology, vol. 79, no. 16, pp. 10247-10257, doi: 10.1128/JVI.79.16.10247-10257.2005.

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Title Mutations that abrogate human immunodeficiency virus type 1 reverse transcriptase dimerization affect maturation of the reverse transcriptase heterodimer
Author(s) Wapling, Johanna
Moore, Katie L.
Sonza, Secondo
Mak, JohnsonORCID iD for Mak, Johnson orcid.org/0000-0002-5229-5707
Tachedjian, Gilda
Journal name Journal of virology
Volume number 79
Issue number 16
Start page 10247
End page 10257
Total pages 11
Publisher American Society for Microbiology
Place of publication Washington, D. C.
Publication date 2005-08
ISSN 0022-538X
1098-5514
Keyword(s) codon
dimerization
gene products
gag
HIV core protein p24
HIV protease
HIV-1 reverse transcriptase
indinavir
mutation
protein precursors
virion
Summary The specific impact of mutations that abrogate human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) dimerization on virus replication is not known, as mutations shown previously to inhibit RT dimerization also impact Gag-Pol stability, resulting in pleiotropic effects on HIV-1 replication. We have previously characterized mutations at codon 401 in the HIV-1 RT tryptophan repeat motif that abrogate RT dimerization in vitro, leading to a loss in polymerase activity. The introduction of the RT dimerization-inhibiting mutations W401L and W401A into HIV-1 resulted in the formation of noninfectious viruses with reduced levels of both virion-associated and intracellular RT activity compared to the wild-type virus and the W401F mutant, which does not inhibit RT dimerization in vitro. Steady-state levels of the p66 and p51 RT subunits in viral lysates of the W401L and W401A mutants were reduced, but no significant decrease in Gag-Pol was observed compared to the wild type. In contrast, there was a decrease in processing of p66 to p51 in cell lysates for the dimerization-defective mutants compared to the wild type. The treatment of transfected cells with indinavir suggested that the HIV-1 protease contributed to the degradation of virion-associated RT subunits. These data demonstrate that mutations near the RT dimer interface that abrogate RT dimerization in vitro result in the production of replication-impaired viruses without detectable effects on Gag-Pol stability or virion incorporation. The inhibition of RT activity is most likely due to a defect in RT maturation, suggesting that RT dimerization represents a valid drug target for chemotherapeutic intervention.
Language eng
DOI 10.1128/JVI.79.16.10247-10257.2005
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, American Society for Microbiology
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047542

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.