Linked Life Data

18662701

Source:http://linkedlifedata.com/resource/pubmed/id/18662701

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2008-9-1
pubmed:abstractText
Deletions in the beta 3-beta 4 hairpin loop of human immunodeficiency virus type 1 reverse transcriptase (RT) are associated with the emergence of multidrug resistance. Common mutational patterns involve the deletion of Asp67 (Delta 67) and mutations such as K70R and T215F or T215Y, or the deletion of Thr69 (Delta 69) and mutations of the Q151M complex. Human immunodeficiency virus type 1 clones containing Delta 69 in a multidrug-resistant sequence background, including the Q151M complex and substitutions K103N, Y181C, M184V, and G190A, showed high-level resistance to all tested nucleoside RT inhibitors. In a multidrug-resistant sequence context, the deletion increases viral replication capacity. By itself, Delta 69 conferred increased susceptibility to beta-d-(+)-3'-azido-3'-deoxythymidine (AZT) and beta-l-(-)-2',3'-dideoxy-3'-thiacytidine resistance. Here, we use transient kinetics to show that, in a wild-type sequence background, Delta 69 does not affect the discrimination between AZT triphosphate and 2'-deoxythymidine 5'-triphosphate, but decreases the catalytic efficiency of the incorporation of beta-l-(-)-2',3'-dideoxy-3'-thiacytidine triphosphate relative to 2'-deoxycytidine 5'-triphosphate. In comparison with the wild-type RT, the Delta 69 mutant showed decreased ability to excise primers terminated with AZT monophosphate in the presence of ATP or pyrophosphate (PPi). These data support the role of the excision mechanism in mediating AZT hypersusceptibility. In addition, we demonstrate that the deletion has no effect on resistance to foscarnet (a PPi analogue) on phenotypic and nucleotide incorporation assays carried out with viral clones and recombinant enzymes, respectively. The results of molecular modeling studies suggest that the side chains of Lys65, Asp67, and Lys219 could play an important role in AZT hypersusceptibility mediated by Delta 69, whereas in the absence of Thr69, local structural rearrangements affecting the beta 3-beta 4 and beta 11a-beta 12 loops of the 66-kDa subunit of the RT could reduce the accessibility of the PPi donor to the terminating nucleotide at the 3' end of the primer.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1089-8638
pubmed:author
pubmed:issnType
Electronic
pubmed:day
3
pubmed:volume
382
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
327-41
pubmed:meshHeading
pubmed-meshheading:18662701-Amino Acid Sequence, pubmed-meshheading:18662701-Anti-HIV Agents, pubmed-meshheading:18662701-Codon, pubmed-meshheading:18662701-Crystallography, X-Ray, pubmed-meshheading:18662701-DNA, Viral, pubmed-meshheading:18662701-Deoxycytosine Nucleotides, pubmed-meshheading:18662701-Drug Resistance, Multiple, Viral, pubmed-meshheading:18662701-Foscarnet, pubmed-meshheading:18662701-HIV Infections, pubmed-meshheading:18662701-HIV Reverse Transcriptase, pubmed-meshheading:18662701-Humans, pubmed-meshheading:18662701-Lamivudine, pubmed-meshheading:18662701-Models, Molecular, pubmed-meshheading:18662701-Molecular Sequence Data, pubmed-meshheading:18662701-Mutation, pubmed-meshheading:18662701-Nucleic Acid Conformation, pubmed-meshheading:18662701-Protein Conformation, pubmed-meshheading:18662701-Reverse Transcriptase Inhibitors, pubmed-meshheading:18662701-Sequence Alignment, pubmed-meshheading:18662701-Sequence Deletion, pubmed-meshheading:18662701-Zidovudine
pubmed:year
2008
pubmed:articleTitle
Mechanistic basis of zidovudine hypersusceptibility and lamivudine resistance conferred by the deletion of codon 69 in the HIV-1 reverse transcriptase coding region.
pubmed:affiliation
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't