Synonymous mutations in stem-loop III of Rev responsive elements enhance HIV-1 replication impaired by primary mutations for resistance to enfuvirtide

Ueno, Makoto; Kodama, Eiichi; Shimura, Kazuya; Sakurai, Yoshio; Kajiwara, Keiko; Sakagami, Yasuko; Oishi, Shinya; Fujii, Nobutaka; Matsuoka, Masao

doi:10.1016/j.antiviral.2009.02.002

Cited by 22 publications

(19 citation statements)

References 40 publications

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“…Interestingly, the eight gp41 residues associated with primary T20 resistance are all localized within the RNA-RRE structure. Some of the resistance mutations have already been found to modify the RRE structure and impair its ability to bind Rev protein, thus reducing the rate of viral replication [4,12,13] . Recently, our group detected in T20-failing patients a frequent occurrence of gp41 primary resistance mutation V38A in association with T18A [13,14] .…”

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confidence: 99%

Genetic and Structural Analysis of HIV-1 Rev Responsive Element Related to V38A and T18A Enfuvirtide Resistance Mutations

et al. 2011

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Background: For the expression of late viral genes, HIV-1 efficiently exploits the nuclear export by using Rev viral protein, which specifically binds the RNA Rev Responsive Element (RRE). This region is contained within the gp120-gp41 encoding sequence. Enfuvirtide is the first approved HIV-1 fusion-inhibitor, and gp41 codons associated with primary enfuvirtide-resistance (amino-acids 36–45) are localized within the RRE structure. We previously found the co-presence of V38A+T18A resistance mutations in patients failing enfuvirtide. Methods: Collecting 476 and 135 HIV-1 B-subtype gp41 sequences from enfuvirtide-naïve and enfuvirtide-treated patients, respectively, two mutations previously found associated with enfuvirtide treatment, T18A and V38A, were analyzed. Moreover, the RNA secondary structure was displayed by CONTRAfold-software and the gp41 evolutionary pathways by a mutagenetic tree. Results: By modeling the RRE structure, we show that the T18 and V38 codons are base pairing within the RRE-stem-IIA, an important domain involved in Rev binding. While a structural RRE impairment in the presence of V38A alone was found, a restoration of the original RRE structure occurred in co-presence of V38A+T18A. By mutagenetic tree analysis, a compensatory evolution confirming our hypothesis on the structural modification mechanism was observed. Conclusion: We show that enfuvirtide pressure may also affect specific RRE domains involved in Rev binding, thus requiring a compensatory evolution able to preserve the secondary structure of the RRE.

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confidence: 99%

Genetic and Structural Analysis of HIV-1 Rev Responsive Element Related to V38A and T18A Enfuvirtide Resistance Mutations

et al. 2011

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“…1B). The D36G substitution has been widely observed in HIV-1 strains and is thought to contribute to efficient replication rather than causing resistance by decreasing binding to the inhibitor (10,27,28). At P-44, we observed the K63N change and a mixture of asparagine and lysine at residue 43 (N43N/K) in gp41.…”

Section: E Nfuvirtide (T-20)mentioning

confidence: 75%

“…K63N is located adjacent to Q64, which was previously shown to be a resistance-associated substitution (32). The synonymous change in V72 (GTG to GTA) may influence the RRE structural stability, as we have previously described (28). With the exception of D153Y, Q199P, and P203S in gp41, all substitutions were observed in the vast majority of T-20-naive patients, indicating that they are natural polymorphisms.…”

Section: E Nfuvirtide (T-20)mentioning

confidence: 92%

“…We previously demonstrated that T-20EK inhibited T-20-resistant variants harboring G36D, V38A, or N43D/K substitutions (28) and that it maintains its strong antiviral effect against HIV-2 (23). T-20EK-resistant variants showed very limited cross-resistance to other novel fusion inhibitors, with the exception of T-20-based peptides, indicating that the combination of T-20EK with other new fusion inhibitors may be suitable for therapy.…”

Section: E Nfuvirtide (T-20)mentioning

confidence: 99%

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HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains

Shimane¹,

Kawaji²,

Miyamoto³

et al. 2013

Antimicrob Agents Chemother

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e T-20EK is a novel fusion inhibitor designed to have enhanced ␣-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors.

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“…In the human genome, most DNA sequences of certain length (e.g., ~100 bases) can fold into a stem-loop secondary structure. Stem-loop structures are important for mRNA translation, transcription termination, virus replication, and mRNA maturation (Ueno et al, 2009;Cai et al, 2010). Deletion or disruption of predicted stemloop structures has been demonstrated to affect minus-strand RNA synthesis, and their complementarity in the minus-strand RNA influences the efficiency of plus-strand synthesis (Frolov et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Effect of mutations in a simian virus 40 PolyA signal enhancer on green fluorescent protein reporter gene expression

Wang¹,

Xf²,

Xy³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Our previous studies have shown that tandem Alu repeats inhibit green fluorescent protein (GFP) gene expression when inserted downstream of the GFP gene in the pEGFP-C1 vector. We found that the 22R sequence (5'-GTGAAAAAAATGCTTTATTTGT-3') from the antisense PolyA (240 bp polyadenylation signal) of simian virus 40, eliminated repression of GFP gene expression when inserted between the GFP gene and the Alu repeats. The 22R sequence contains an imperfect palindrome; based on RNA structure software prediction, it forms an unstable stem-loop structure, including a loop, a first stem, a bulge, and a second stem. Analysis of mutations of the loop length of the 22R sequence showed that the three-nucleotide loop (wild-type, 22R) induced much stronger GFP expression than did other loop lengths. Two mutations, 4TMI (A7→T, A17→T) and 5AMI (A6→T, T18→A), Effect of enhancer mutations on GFP reporter gene expression which caused the base type changes in the bulge and in the second stem in the 22R sequence, induced stronger GFP gene expression than 22R itself. Mutation of the bulge base (A17→T), leading to complete complementation of the stem, caused weaker GFP gene expression. Sequences without a palindrome (7pieA, 5'-GTGAAAAAAATG CAAAAAAAGT-3', 7pieT, 5'-GTGTTTTTTTTGCTTTTTTTGT-3') did not activate GFP gene expression. We conclude that an imperfect palindrome affects and can increase GFP gene expression.

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Synonymous mutations in stem-loop III of Rev responsive elements enhance HIV-1 replication impaired by primary mutations for resistance to enfuvirtide

Cited by 22 publications

References 40 publications

Genetic and Structural Analysis of HIV-1 Rev Responsive Element Related to V38A and T18A Enfuvirtide Resistance Mutations

Genetic and Structural Analysis of HIV-1 Rev Responsive Element Related to V38A and T18A Enfuvirtide Resistance Mutations

HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains

Effect of mutations in a simian virus 40 PolyA signal enhancer on green fluorescent protein reporter gene expression

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