Impact of Amino Acid Variations in Gag and Protease of HIV Type 1 CRF01_AE Strains on Drug Susceptibility of Virus to Protease Inhibitors

Jinnopat, Piyamat; Isarangkura-na-ayuthaya, Panasda; Utachee, Piraporn; Kitagawa, Yukiko; Silva, U Chandimal de; Siripanyaphinyo, Uamporn; Kameoka, Yoko; Tokunaga, Kenzo; Sawanpanyalert, Pathom; Ikuta, Kazuyoshi; Auwanit, Wattana; Kameoka, Masanori

doi:10.1097/qai.0b013e3181b4b18c

Cited by 13 publications

(22 citation statements)

References 54 publications

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“…These results support and add to previous published work suggesting that changes within Gag have a role in both the replication capacity of drug-resistant protease and, perhaps more importantly, in the drug susceptibility of viruses with no mutations in protease (6,12,15,28). While we have identified three specific changes (R76K, Y79F, and T81A) that have a role in replication capacity and PI susceptibility, it is important to note that none of the other viruses studied elsewhere shares all three of these changes (12,15). It is, however, interesting to note that virus a MA 1, matrix mutation position 1; PR 1, protease mutation position 1. b MA 2, matrix mutation position 2. c Z score: (sequence data JI score Ϫ random model JI score)/sequence data JI score SE.…”

Section: Discussionsupporting

confidence: 90%

“…AE-Gag62 shares the same K30R (not studied here), R76K, and Y79F changes as our mutant, and these authors report that the amino-terminal region of Gag from this virus caused reduced PI susceptibility (15). Some of the reduced PI susceptibility has been attributed to K165 (within capsid) of the CRF01_AE virus studied (not present in our mutant).…”

Section: Discussionsupporting

confidence: 71%

“…There is increasing evidence that differences in PI susceptibility can be influenced by natural variation within HIV, such as differences in gag. The PI susceptibility of full-length gag and protease from wild-type (treatment-naïve) HIV-1 strains of different subtypes varies from that of standard subtype B. Gag was again shown to be the main contributor to this phenotype (12,15).…”

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confidence: 99%

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Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity

Parry¹,

Kolli

Cane³

et al. 2011

Antimicrob Agents Chemother

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Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutations in gag, particularly within matrix protein can restore replication capacity and further reduce protease inhibitor drug susceptibility when coexpressed with a drug-resistant (mutant) protease. The matrix protein of this patient-derived virus was studied in order to identify specific changes responsible for this phenotype. Three amino acid changes in matrix (R76K, Y79F, and T81A) had an impact on replication capacity as well as drug susceptibility. Introduction of these three changes into wild-type (WT) matrix resulted in an increase in the replication capacity of the protease mutant virus to a level similar to that achieved by all the changes within the mutant matrix and part of the capsid protein. Pairs of changes to wild-type matrix led to an increased replication capacity of the protease mutant (although less than with all three changes). Having only these three changes to matrix in a wild-type virus (with wild-type protease) resulted in a 5-to 7-fold change in protease inhibitor 50% effective concentration (EC 50 ). Individual changes did not have as great an effect on replication capacity or drug susceptibility, demonstrating an interaction between these positions, also confirmed by sequence covariation analysis. Molecular modeling predicts that each of the three mutations would result in a loss of hydrogen bonds within ␣-helix-4 of matrix, leading to the hypothesis that more flexibility within this region or altered matrix structure would account for our findings.Current British HIV Association (BHIVA) and other guidelines for highly active antiretroviral therapy (HAART) in the treatment of HIV and AIDS recommend first-line therapy with three active drugs: two nucleoside reverse transcriptase (RT) inhibitors and a nonnucleoside RT inhibitor. Protease inhibitors (PIs) are used with two active RT inhibitors in second-line therapy after the failure of first-line therapy (11). PIs are some of the most potent of the antiretroviral drugs in HIV clinical practice. Resistance to PIs develops by the accumulation of mutations within the protease gene that change amino acids within the enzymatic active site, reducing the binding of the inhibitor. Many of these primary PI resistance mutations have a negative effect on virus fitness or replication capacity, resulting in further secondary mutations that do not cause resistance themselves but instead increase the replication capacity of the resistant virus (2-5, 20, 22, 26). HIV protease cleaves Gag and Gag-Pol polyproteins, resulting in viral maturation after cellular release. Mutations within the Gag protein, particularly at the cleavage sites (cleavage site mutations [CSMs]) have also been associated with the recovery of replication capacity (9,10,24,31,35) as well as with PI resistance without protease mutations (27). Structural analysis showed that the A431V CSM has incr...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

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Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity

Parry¹,

Kolli

Cane³

et al. 2011

Antimicrob Agents Chemother

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“…However, the results of these two studies are difficult to compare because of the different protease inhibitor regimens used (fosamprenavir-atazanavir/r or saquinavir-atazanavir/r therapy versus lopinavir/r monotherapy) and the times of assessment of virological failure (week 16 versus week 96). Moreover, reduced susceptibilities to protease inhibitors of CRF01_AE strains, showing polymorphisms in the protease and gag cleavage sites, have been recently demonstrated (21).…”

Section: Discussionmentioning

confidence: 97%

Gag Mutations Can Impact Virological Response to Dual-Boosted Protease Inhibitor Combinations in Antiretroviral-Naïve HIV-Infected Patients

Larrouy

Chazallon

Landman

et al. 2010

Antimicrob Agents Chemother

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ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P ‫؍‬ 0.04) and 449 (p1/p6 gag ) (P ‫؍‬ 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6 pol ) was associated with virological response (P ‫؍‬ 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

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“…Recently, we published data showing the direct effect of mutations at positions 76, 79 and 81 within MA (matrix) at the Nterminus of Gag on PI susceptibility (Parry et al, 2009;Parry et al, 2011). Other studies also showed that changes in CA (capsid) at position 165, within the N-terminus of Gag, affected PI susceptibility (Jinnopat et al, 2009;Kameoka et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Contribution of Gag and protease to variation in susceptibility to protease inhibitors between different strains of subtype B human immunodeficiency virus type 1

Sutherland

Mbisa

Cane

et al. 2014

Journal of General Virology

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Recent reports have shown that human immunodeficiency virus type 1 (HIV-1) Gag can directly affect susceptibility to protease inhibitors (PIs) in the absence of known resistance mutations in protease. Inclusion of co-evolved Gag alongside protease in phenotypic drug susceptibility assays can alter PI susceptibility in comparison with protease with a WT Gag. Using a single-replication-cycle assay encompassing full-length Gag together with protease we demonstrated significant variation in PI susceptibility between a number of PI-naïve subtype B viruses. Six publicly available subtype B molecular clones, namely HXB2, NL4-3, SF2, YU2, JRFL and 89.6, displayed up to nine-fold reduced PI susceptibility in comparison with the assay reference strain. For two molecular clones, YU2 and JRFL, Gag contributed solely to the observed reduction in susceptibility, with the N-terminal region of Gag contributing significantly. Gag and protease from treatment-naïve, patient-derived viruses also demonstrated significant variation in susceptibility, with up to a 17-fold reduction to atazanavir in comparison with the assay reference strain. In contrast to the molecular clones, protease was the main determinant of the reduced susceptibility. Common polymorphisms in protease, including I13V, L63P and A71T, were shown to contribute to this reduction in PI susceptibility, in the absence of major resistance mutations. This study demonstrated significant variation in PI susceptibility of treatment-naïve patient viruses, and provided further evidence of the independent role of Gag, the protease substrate and in particular the N-terminus of Gag in PI susceptibility. It also highlighted the importance of considering co-evolved Gag and protease when assessing PI susceptibility.

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Impact of Amino Acid Variations in Gag and Protease of HIV Type 1 CRF01_AE Strains on Drug Susceptibility of Virus to Protease Inhibitors

Abstract: Our results suggest that amino acid variations in AE-PR and AE-Gag play roles in determining the drug susceptibility of CRF01_AE viruses to PIs.

Cited by 13 publications

References 54 publications

Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity

Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity

Gag Mutations Can Impact Virological Response to Dual-Boosted Protease Inhibitor Combinations in Antiretroviral-Naïve HIV-Infected Patients

Contribution of Gag and protease to variation in susceptibility to protease inhibitors between different strains of subtype B human immunodeficiency virus type 1

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