Result: SQV shows a shorter hydrogen bond of 3.1 A with the carbonyl oxygen of Gly27 compared to a 3.6 A long interaction in the wild type PR, similar to that described recently in the SQV complex with the L76V single mutant.
Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring.
PMID: 22401672
2012
Journal of medicinal chemistry
Abstract: Crystal structures at resolutions of 1.25-1.55 A were analyzed for complexes of 1 with the Method: HIV-1 PR point mutants (I47V, L76V, V82A and N88D) were constructed using optimized HIV-1 PR template with Quikchange site-directed mutagenesis kit (Stratagene).
Result: Influence of distal N88D and L76V mutations on the conformation of Asp30.
Result: Overall, the L76V and N88D mutations appear to disrupt the internal van der Waals contacts and hydrogen bonding network, which may alter the stability of the enzyme with minimal effect on the binding of inhibitors.
Virologic failures on initial boosted-PI regimen infrequently possess low-level variants with major PI resistance mutations by ultra-deep sequencing.
Abstract: Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV.
Abstract: The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1).
Result: Of the 12 specimens that had ultra deep sequencing of only the protease gene, 4/12 (33.3%) had low level PI mutations: F53L(2),
Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor.
PMID: 22258921
2012
The Journal of antimicrobial chemotherapy
Abstract: One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3).
Interpretation of genotypic resistance to predict darunavir/ritonavir failure in antiretroviral experienced patients.
PMID: 22067663
2012
Journal of acquired immune deficiency syndromes (1999)
Abstract: Four mutations (V32I, I50V, L76V, I84V) were predictive of failure, the hazard ratio progressively increased by detecting 1 (hazard ratio: 2.0, 95% confidence interval: 1.3 to 3.0), 2 (3.6, 2.0 to 6.6), or 3 of them (9.7, 2.8 to 33.5).
Virological response to darunavir in patients infected with HIV is linked to darunavir resistance-associated mutations corrected by the count of mutations with positive impact and is not associated with pharmacological and combined virological/pharmacological parameters.
PMID: 21545648
2012
Fundamental & clinical pharmacology
Abstract: Darunavir GIQ is defined as the ratio between darunavir trough plasma concentration and the count of darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) corrected or not corrected by the count of mutations with positive impact (V82A and E35D).
Lopinavir/ritonavir resistance in patients infected with HIV-1: two divergent resistance pathways?
Abstract: In contrast, I54V, G73S and L90M were less prevalent in viruses L76V positive than L76V negative (I54V, 42% vs. 83%, P = 0.01; G73S, 0% vs. 33%, P = 0.02; L90M, 25% vs. 83%, P = 0.0006).
Abstract: In univariate analyses, of the mutations found in _10% of patients, L89M and Q58E were more prevalent in viruses L76V positive than L76V negative (L89M, 42% vs. 0%, P = 0.0007; Q58E, 50% vs. 25%, P = 0.1).
Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.
Abstract: BACKGROUND: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V.
Abstract: Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations.
Abstract: CONCLUSIONS: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance.
Abstract: In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of
Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.
Abstract: Although the L76V mutation significantly slows the N-terminal autoprocessing of the precursor TFR-PR(L76V) to give rise to the mature PR(L76V), the coselected M46I mutation counteracts the effect by enhancing this rate but renders the TFR-PR(M46I/L76V) precursor less responsive to inhibition by 6 muM LPV while preserving inhibition by SQV and DRV.
Abstract: Crystal structures of PR(L76V) in complexes with DRV and SQV were determined at resolutions of 1.45-1.46 A.
Abstract: Differential scanning calorimetry showed decreases in T(m) of 12C for PR(
Interpretation of genotypic HIV-1 resistance to darunavir and virological response: validation of available systems and of a new score.
Abstract: The DRV-2009 score V11I+L33F+R41K+I47V+2*I50V+2*I54M+K55R+D60E+L74P+L76V+N88D+2*L89V-L10I/V-I13V-G16E-G48V-F53I/L-I62V-I66F-V77I (<0 indicating susceptibility, 0-1 intermediate resistance and >=2 resistance) correlated with VR in the derivation set (n=132, R=0.395; P<0.001).
HIV mutation literature information.
PMID: 
2012
Biochemistry
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