Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations.
PMID: 20462946
2010
The Journal of antimicrobial chemotherapy
Method: We also examined the extent to which the 52 NNRTI-selected mutations covaried with mutations at 12 major nucleoside reverse transcriptase inhibitor (NRTI) resistance positions, including M41L, K65R, D67N, T69S_SS, K70E, K70R, L74V, L74I, V75M/T, Y115F, Q151M, M184V/I,
Result: Another notable, though weaker, positive correlation exists between K65R and Y181C.
Clonal resistance analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and tenofovir.
Method: Samples were available for 9/10 patients who had both M184V and K65R mutations detected by standard genotype, either with or without wild-type as a mixture.
Res
Result: K65R was detected in 105 (51%) sequences.
Result: K65R/M184I double-mutant and wild-type were detected only once each.
Result: Each sample had both K65R and M184V; six samples had 65R present as a mixture with wild-type K65, and three of these six contained a mixture of 184V with wild-type M184.
Result: For ddI, TNV, and ABC, the mean IC50 values for K65R/M184V double-mutants were significantly higher than for M184V single-mutants (p <0.001).
Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naive subjects in the CASTLE study.
Result: Of the 141 subjects with a UDS result, 35 (24.8%) had a nucleoside(tide) reverse transcriptase inhibitor N(t)RTI(s) TDR; 26 of these had a thymidine analog mutation (TAM), 9 had a M184V/I, and 2 had a variant with a K65R.
Result: Six of the 9 experienced VF; 4 of these also had TAMs, and 1 had K65R+TAMs (Table 3).
Result: Specific TDR patterns and levels for subjects with a M184V/I and K65R are shown in Table 4.
Result: Three (2.1%) subjects had M184V and multiple TAMs, and all were VF; 2 subjects had a K65R at baseline by UDS (1 VF and 1 VS) (Table 3).
Table: K65R
Prevalence of M184V and K65R in proviral DNA from PBMCs in HIV-infected youths with lamivudine/emtricitabine exposure.
Discussion: Although K65R results in an increase in misinsertion fidelity, there is an additional decrease in mismatch extension from some termini, which is due to a 10-fold increase in dNTP Kd compared to the wild-type.
Discussion: As expected, the K65R substitution has no, or little, effect on the binding of either a correct or incorrect dNTP; one of the guanidinium nitrogens of the Arg65 residue is positioned to coordinate the incoming dNTP similarly to Lys65 in the wild type.
Discussion: Both the K65A and K65R mutations lead to a decrease in mismatch extension efficiency compared to the wild-type enzyme.
Discussion: In the context of misinsertion, the Arg72, with less freedom of movement due to the K65R substitution, may be less able to coordinate
Nucleic acid template and the risk of a PCR-Induced HIV-1 drug resistance mutation.
Result: Although limiting dilution sequencing did not detect K65R, it did detect each of the other 33 nucleotide and three amino acid mutations that were present in more than 1.0% of UDPS reads in these two samples.
Result: Among the subtype B samples, K65R was detected in more than 1.0% of reads in a sample with a complex mixture of KKK nucleotide variants including AAA-AAG-AAA (the second-most common subtype C pattern) in 38% of reads, AAG-AAA-AAA (the most common subtype B pattern) in 7% of reads, and an uncommon pattern AAG-AAG-AAA in 50% of reads.
Result: Among the subtype C samples, K65R was detected in at least 1.0% of reads in eight samples, including 7 of 11 with the most common subtype C pattern and the one sample with the second-most common subtype C pattern.
Result: Clonal analysis of two subtype C viruses for which more than 2.0% of UPDS reads contained
Prevalence of M184V and K65R in proviral DNA from PBMCs in HIV-infected youths with lamivudine/emtricitabine exposure.
Abstract: RT-sequence revealed mutations at position
Abstract: CONCLUSIONS: In virologically failing patients due to K65R- and other non-thymidine-mutations, simple regimen intensification with zidovudine resulted in sustained HIV-1 suppression.
Abstract: METHODS: We identified HIV-1 infected patients from a large treatment cohort who experienced virological failure (HIV-1 RNA >1000 copies/mL) with evidence of resistance mutations including the K65R, but without thymidine analogue mutations (TAMs) in genotypic resistance assay.
Abstract: OBJECTIVES: The reverse transcriptase (RT)-mutation K65R limits further therapeutic options and has been selected by unfavorable RT-combinations.
Genetic characterization of HIV type 1 among patients with suspected immune reconstitution inflammatory syndrome after initiation of antiretroviral therapy in Kenya.
PMID: 20624074
2010
AIDS research and human retroviruses
Abstract: These included nucleoside reverse transcriptase inhibitor (RTI) mutations: M41L, K65R, D67N, K70R, M184V, and K219Q, and nonnucleoside RTI mutations: K101P, L100I, K103N, and Y181C.
Evolution of drug resistance during 48 weeks of zidovudine/lamivudine/tenofovir in the absence of real-time viral load monitoring.
PMID: 20686411
2010
Journal of acquired immune deficiency syndromes (1999)
Abstract: K65R was detected in 8 of 63 (13%) patients and was negatively associated with number of TAMs (P = 0.01) but not viral subtype (P = 0.30).
Abstract: CONCLUSIONS: A high rate of acquisition of TAMs, but not of K65R, among patients with prolonged viraemia was observed.
Proteochemometric modeling of the susceptibility of mutated variants of the HIV-1 virus to reverse transcriptase inhibitors.
Abstract: The most deleterious mutations were K65R, Q151M, M184V/I, and T215Y/F, each of them decreasing susceptibility to most of the NRTIs.
Result: Figure 3 presents screenshots of outputs from the web page, illustrating the predicted susceptibilities for two patterns of mutations: K65R+M184V (Panel A) and M41L+L210W+T215Y (Panel B).
Result: For example, mutations M184V/I and K65R, which are the most deteriorating for 3TC and FTC, lead to significant increase in susceptibility to AZT, thus suggesting a benefit of combining these inhibitors.
Analysis of resistance testing in South Trinidad.
PMID: 21355515
2010
The West Indian medical journal
Abstract: Poor adherence to antiretroviral therapy (ART) has resulted in the development of multidrug resistant HIV Resistance testing done on 40 samples showed that 64.8% of patients had K103 mutation, 75.6% of patients had M184 mutations and 62% of patients showed resistance to tenofovir suggesting that the K65R mutation was highly likely to be present.
HIV mutation literature information.
PMID: 
2010
The Journal of antimicrobial chemotherapy
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