Identification and Structural Characterization of I84C and I84A Mutations That Are Associated with High-Level Resistance to Human Immunodeficiency Virus Protease Inhibitors and Impair Viral Replication

Mo, Hongmei; Parkin, Neil; Stewart, Kent D.; Lu, Liangjun; Dekhtyar, Tatyana; Kempf, Dale J.; Molla, Akhteruzzaman

doi:10.1128/aac.00690-06

Cited by 13 publications

(14 citation statements)

References 19 publications

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“…Interestingly, a predominant presence of PI-associated Gag substitutions at the flexible C-terminal domain of Gag ( Figure 2B) leads us to suggest the hypothesis that PI-associated Gag substitutions tend to emerge in the structural flexible regions. These Gag substitutions can emerge along with protease drug resistance mutations as shown in our longitudinal sequence analysis (Figure 1, Additional file 1: Table S2) and previous studies [21,22]. Future studies are still needed to investigate the significance of coevolution between Gag substitutions and protease resistance mutations.…”

Section: Resultssupporting

confidence: 53%

HIV-1 Gag C-terminal amino acid substitutions emerging under selective pressure of protease inhibitors in patient populations infected with different HIV-1 subtypes

Verheyen

Theys

et al. 2014

Retrovirology

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Section: Resultssupporting

confidence: 53%

HIV-1 Gag C-terminal amino acid substitutions emerging under selective pressure of protease inhibitors in patient populations infected with different HIV-1 subtypes

Verheyen

Theys

et al. 2014

Retrovirology

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“…The L76V mutation is selected by M46I, I54V, V82F, I84A, and L90M with IDV (1,15,21,23,28,30, 31) and M46I, I54V, V82F, I84A, L90M, I50V, and N88G with LPV (1,15,[21][22][23]30). However, the L76V mutation itself seems to have an important impact on resistance, at least for LPV.…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Lambert-Niclot¹,

Flandre

Canestri

et al. 2008

Antimicrob Agents Chemother

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The objective of this study was to characterize the mutations selected by darunavir (DRV) use in protease inhibitor (PI)-experienced patients and the associated factors. We analyzed treatment failure in 54 PIexperienced human immunodeficiency virus (HIV)-infected patients on a DRV-and ritonavir-containing regimen. Viral genotyping was carried out at the baseline, at between 1 and 3 months of treatment, and at between 3 and 6 months of treatment to search for the selection of mutations conferring resistance to PIs. The median baseline HIV RNA level was 4.9 log 10 copies/ml, and the median CD4 count was 87 cells/mm 3 . At the baseline, the median numbers of resistance mutations were as follows: 3 DRV resistance mutations, 4 major PI resistance mutations, and 10 minor PI resistance mutations. The most common mutations that emerged at rebound included V32I (44%), I54M/L (24%), L33F (25%), I84V (21%), and L89V (12%). Multivariate analysis showed that higher baseline HIV RNA levels and smaller numbers of nucleoside reverse transcriptase inhibitor simultaneously used with DRV were associated with a higher risk of DRV resistance mutation selection. By contrast, L76V, a known DRV resistance mutation, was found to decrease the risk of selection of another DRV resistance mutation. The occurrence of virological failure while a patient was on DRV was associated with the selection of mutations that increased the level of DRV resistance without affecting susceptibility to tipranavir (TPV). In these PI-treated patients who displayed treatment failure while they were on a DRV-containing regimen, we confirmed the set of emerging mutations associated with DRV failure and identified the factors associated with the selection of these mutations. TPV susceptibility does not seem to be affected by the selection of a DRV resistance mutation.Virological rebound during antiretroviral treatment is often associated with the emergence of drug resistance, compromising both current and future therapy. The resistance of human immunodeficiency virus (HIV) to protease inhibitors (PIs) generally involves the accumulation of primary and secondary mutations within and outside of the active site of the retroviral protease, sometimes accompanied by mutations in one or more gag cleavage sites (3,11,19,25). The patterns of mutation selected by most of the PIs currently available have been characterized (3,12,19,25,29). In general, individual viral mutations generate only modest changes in phenotypic susceptibility to PIs. However, more than 20% of the 99 amino acids comprising the HIV protease homodimer have been shown to mutate under the selection pressure exerted by drugs (10, 24). Patients with PI-resistant HIV therefore often have viruses with highly complex genotypic patterns. Different PIs may select different primary mutations, but the secondary mutations observed tend to be common to the entire PI class, potentially limiting the success of subsequent PI treatment following the failure of any PI-containing regimen (3,12,19,25,29).The HIV type 1 (...

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“…V82AFST, and I84AV (10,14,17,21,23,31,34,35). Additionally, G48M, and I54AST had a fold change factor of Ͼ2 in the VircoLab analysis (46).…”

Section: Figmentioning

confidence: 99%

“…Eight of the 21 mutations associated with decreased SQV susceptibility were previously reported to be selected by SQV in vitro or in vivo or to decrease SQV susceptibility: G48V, F53L, I54TV, G73S, I84AV, and L90M (9,31,40,47,49). Additionally, G48M, I54AS, and G73T had a fold change factor of Ͼ2 in the VircoLab analysis (46).…”

Section: Figmentioning

confidence: 99%

HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

Rhee

Taylor

Fessel

et al. 2010

Antimicrob Agents Chemother

185

205

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The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.HIV-1 protease inhibitors (PIs) are the mainstays of salvage therapy. As the number of licensed PIs has increased, it has become important to identify whether and how each PI-selected mutation affects cross-resistance to each of the other PIs. In a previous study (41), we previously applied several data mining approaches to assess associations between HIV-1 protease genotype and phenotype test results for the first-generation PIs: amprenavir (APV), the active component of the prodrug fosamprenavir (FPV), atazanavir (ATV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), and saquinavir (SQV). Specifically, we used a data set containing about 300 susceptibility results for ATV, 500 for LPV, and 800 for FPV, IDV, NFV, and SQV (41). We used a predefined list of PIselected mutations in this previous study to reduce the number of independent variables influencing PI susceptibility.Here we analyze a data set that contains between 1,600 and 2,600 isolates tested for susceptibility to the first-generation PIs and about 600 and 1,200 isolates tested for susceptibility to darunavir (DRV) and tipranavir (TPV), respectively. We use two regression methods in tandem: one to identi...

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Identification and Structural Characterization of I84C and I84A Mutations That Are Associated with High-Level Resistance to Human Immunodeficiency Virus Protease Inhibitors and Impair Viral Replication

Cited by 13 publications

References 19 publications

HIV-1 Gag C-terminal amino acid substitutions emerging under selective pressure of protease inhibitors in patient populations infected with different HIV-1 subtypes

HIV-1 Gag C-terminal amino acid substitutions emerging under selective pressure of protease inhibitors in patient populations infected with different HIV-1 subtypes

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

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