Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group.
PMID: 10720512
2000
The Journal of infectious diseases
Abstract: A total of 51% of subjects showed new mutations at any of codons K65R, L74V, and M184V after abacavir monotherapy, compared with 11% who received zidovudine/abacavir.
Abstract: Abacavir alone in vitro selected for mutations at HIV RT codons K65R, L74V, Y115F, and M184V.
Mutational analysis of Lys65 of HIV-1 reverse transcriptase.
Abstract: Furthermore, the K65A, K65Q and K65E mutant enzymes are 100-fold less sensitive to all dideoxynucleoside triphosphate ('ddNTP') inhibitors, whereas the K65R mutation results in a selective 10-fold decrease in binding of ddCTP and ddATP only.
Abstract: In order to biochemically define the function of RT Lys(65), we have used site-specific mutagenesis to generate RT with a variety of substitutions at this position, including K65E, K65Q, K65A and K65R.
Abstract: The pH optimum for the DNA polymerase activity of K65E RT was
Prevalence of M184V and K65R in proviral DNA from PBMCs in HIV-infected youths with lamivudine/emtricitabine exposure.
PMID: 10833521
2000
The Journal of biological chemistry
Abstract: An in vitro dNTP exclusion assay revealed an increased fidelity for K65R RT compared with wild-type RT, but little change for L74V RT.
Abstract: Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variants with the K65R or L74V substitution display resistance to several nucleoside analogs.
Abstract: It is speculated that the increased fidelity of K65R RT is due to an altered interaction with the dNTP substrate.
Abstract: Modeling the substitutions into the x-ray structure of the ternary complex revealed that the major influence of Leu(74) in stabilizi
In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine.
PMID: 10858331
2000
Antimicrobial agents and chemotherapy
Abstract: Cloning and DNA sequencing of the RT region from the first resistant isolate identified a K65R mutation (AAA to AGA) in 10 of 10 clones.
Abstract: However, the combination of AZT with DXG or its orally bioavailable prodrug (-)-beta-D-2, 6-diaminopurine-dioxolane should be explored because of the suppressive effects of the K65R and L74V mutations on AZT resistance.
Abstract: However, when introduced into a genetic background for AZT resistance (D67N, K70R, T215Y, T219Q), the K65R mutation reversed the AZT resistance.
Abstract: The K65R mutation also conferred greater than threefold cross-resistance to 2',3'-dideoxycytidine
Ab initio molecular dynamics studies on HIV-1 reverse transcriptase triphosphate binding site: implications for nucleoside-analog drug resistance.
Abstract: Absence of this interaction in Lys65-->Arg HIV-1 RT might play a prominent role in the resistance of this mutant for nucleoside analogs (Gu Z et al., 1994b, Antimicrob Agents Chemother 38:275-281; Zhang D et al., 1994, Antimicrob Agents Chemother 38:282-287).
Selection of resistance-conferring mutations in HIV-1 by the nucleoside reverse transcriptase inhibitors (+/-)dOTC and (+/-)dOTFC.
Abstract: In contrast, a mutation of lysine to arginine at position 65 (K65R) was found in variants selected with (+/-)dOTFC.
Abstract: Studies with mutated recombinant HXB2D-M184V and -K65R confirmed that these mutations are important for phenotypic resistance in MT-2 cells.
9-[2-(Phosphonomethoxy)propyl]adenine (PMPA) therapy prolongs survival of infant macaques inoculated with simian immunodeficiency virus with reduced susceptibility to PMPA.
PMID: 10103184
1999
Antimicrobial agents and chemotherapy
Abstract: In conclusion, this study demonstrates that although SIVmac mutants with the PMPA-selected K65R mutation in RT were highly virulent, PMPA treatment still offered strong therapeutic benefits.
Abstract: To study directly the virulence and clinical implications of these SIV mutants, two uncloned SIVmac isolates with similar fivefold reduced in vitro susceptibilities to PMPA but distinct RT genotypes, SIVmac055 (K65R, N69T, R82K A158S,S211N) and SIVmac385 (K65R, N69S, I118V), were each inoculated intravenously into six newborn rhesus macaques; 3 weeks later, three animals of each group were started on
In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA.
Abstract: In agreement with the cell culture findings, Escherichia coli-expressed K65R RT showed fivefold reduced susceptibility to PMPA diphosphate, the active moiety of PMPA.
Abstract: Interestingly, lamivudine-resistant viruses expressing the M184V RT mutation showed wild-type to slightly increased susceptibility to PMPA in vitro and addition of the M184V mutation to HIV with the K65R mutation resulted in reversion to wild-type susceptibility for PMPA.
Abstract: Sequence analysis of the reverse transcriptase (RT) genes from four of 15 RT clones demonstrated the presence of a K65R substitution in
Endogenous reverse transcriptase assays reveal synergy between combinations of the M184V and other drug resistance-conferring mutations in interactions with nucleoside analog triphosphates.
Abstract: The K65R mutation, that confers low level resistance to both 3TC and ddC, can also restore sensitivity to AZT.
Abstract: To explore this subject further, we have used an endogenous RT reaction to study mutated viruses containing M184V alone or M184V combined with each of the K65R, E89G or both the M41L and T215Y substitutions.
Abstract: We now show that viruses containing both M184V and K65R displayed synergistic resistance to 3TC triphosphate (3TCTP), while the same combination yielded the same level of resistance to ddC triphosphate (ddCTP) as that manifested by K65R alone.
Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl)PMPA against various drug-resistant human immunodeficiency virus strains.
PMID: 9624498
1998
Antimicrobial agents and chemotherapy
Abstract: K65R virus also showed reduced susceptibility to bis(poc)PMPA, although the prodrug could still inhibit these viruses at submicromolar, nontoxic concentrations.
Abstract: Among a large panel of drug-resistant HIV type 1 variants, only the K65R virus was resistant to PMPA.
HIV mutation literature information.
PMID: 
2000
The Journal of infectious diseases
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