Single Nucleotide Polymorphism Induces a Positive Selection Pressure at Gag-Pol Sites in Human Immunodeficiency Virus Favoring Drug Resistance Mutations

Zahra, Amreen; Saleem, Muhammad; Javed, Hasnain; Khan, Muhammad Azmat Ullah; Naveed, Muhammad; Shakoori, A. R.

doi:10.17582/journal.pjz/20200525130507

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…The proportion of URFs among the pol genotyped isolates was significantly higher than Gag. This increased prevalence strikes towards an increased vulnerable hypervirulency in the HIV virus (Zahra et al, 2021).…”

Section: Hiv Genotyping Analysismentioning

confidence: 99%

Prevalence of Bovine Herpes Virus 1 in Yaks (Bos grunniens) from the Qinghai-Tibetan Plateau in China: A Meta-analysis

Chen¹

2022

PJZ

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Section: Hiv Genotyping Analysismentioning

confidence: 99%

Prevalence of Bovine Herpes Virus 1 in Yaks (Bos grunniens) from the Qinghai-Tibetan Plateau in China: A Meta-analysis

Chen¹

2022

PJZ

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“…To our knowledge, all PR variants that cause resistance to PI's exhibit dramatically reduced enzyme activity [27][28][29][30]. Many studies have found that cleavage sites in Gag co-evolve with drug resistant mutations in PR, indicating that the mutations in the cleavage sites may compensate for reduced enzyme activity of PR [31][32][33][34][35][36][37][38][39]. Cutsite compensatory evolution has most commonly been associated with the NC/p1 and p1/p6 sites.…”

Section: Introductionmentioning

confidence: 99%

Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease

Samant

Nachum

Tsepal

et al. 2022

Preprint

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The infectivity of HIV-1 requires its protease cleave multiple cut-sites with low sequence similarity. The diversity of cleavage sites has made it challenging to investigate the underlying sequence properties that determine binding and turnover of substrates by PR. We engineered a mutational scanning approach utilizing yeast display, flow cytometry, and deep sequencing to systematically measure the impacts of all individual amino acid changes at 12 positions in three different cut-sites (MA/CA, NC/p1, and p1/p6). The resulting fitness landscapes revealed common physical features that underlie cutting of all three cut-sites at the amino acid positions closest to the scissile bond. In contrast, positions more than two amino acids away from the scissile bond exhibited a strong dependence on the sequence background of the rest of the cut-site. We observed multiple amino acid changes in cut-sites that led to faster cleavage rates, including a preference for negative charge five and six amino acids away from the scissile bond at locations where the surface of protease is positively charged. Analysis of individual cut sites using full-length matrix-capsid proteins indicate that long-distance sequence context can contribute to cutting efficiency such that analyses of peptides or shorter engineered constructs including those in this work should be considered carefully. This work provides a framework for understanding how diverse substrates interact with HIV-1 protease and can be extended to investigate other viral proteases with similar properties.

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“…[28][29][30][31] Many studies have found that cleavage sites in Gag coevolve with drug resistant mutations in PR, indicating that the mutations in the cleavage sites may compensate for reduced enzyme activity of PR. [32][33][34][35][36][37][38][39][40] Cut-site compensatory evolution has most commonly been associated with the NC/p1 and p1/p6 sites.…”

Section: Introductionmentioning

confidence: 99%

“…To our knowledge, all PR variants that cause resistance to PI's exhibit dramatically reduced enzyme activity 28–31 . Many studies have found that cleavage sites in Gag co‐evolve with drug resistant mutations in PR, indicating that the mutations in the cleavage sites may compensate for reduced enzyme activity of PR 32–40 . Cut‐site compensatory evolution has most commonly been associated with the NC/p1 and p1/p6 sites.…”

Section: Introductionmentioning

confidence: 99%

Sequence dependencies and biophysical features both govern cleavage of diverse cut‐sites by HIV protease

et al. 2022

View full text Add to dashboard Cite

The infectivity of HIV-1 requires its protease (PR) cleave multiple cut-sites with low sequence similarity. The diversity of cleavage sites has made it challenging to investigate the underlying sequence properties that determine binding and turnover of substrates by PR. We engineered a mutational scanning approach utilizing yeast display, flow cytometry, and deep sequencing to systematically measure the impacts of all individual amino acid changes at 12 positions in three different cut-sites (MA/CA, NC/p1, and p1/p6). The resulting fitness landscapes revealed common physical features that underlie cutting of all three cut-sites at the amino acid positions closest to the scissile bond. In contrast, positions more than two amino acids away from the scissile bond exhibited a strong dependence on the sequence background of the rest of the cut-site. We observed multiple amino acid changes in cut-sites that led to faster cleavage rates, including a preference for negative charge five and six amino acids away from the scissile bond at locations where the surface of protease is positively charged. Analysis of individual cut sites using full-length matrix-capsid proteins indicate that long-distance sequence context can contribute to cutting efficiency such that analyses of peptides or shorter engineered constructs including those in this work should be considered carefully. This work provides a framework for understanding how diverse substrates interact with HIV-1 PR and can be extended to investigate other viral PRs with similar properties.

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Single Nucleotide Polymorphism Induces a Positive Selection Pressure at Gag-Pol Sites in Human Immunodeficiency Virus Favoring Drug Resistance Mutations

Abstract: Authors' Contribution AZ conceived, designed and wrote the research article. MAS proofread the study. HJ confirmed the data and sources. MAUK, MN and ARS helped in writing of the article and analysis of data.

Cited by 7 publications

References 31 publications

Prevalence of Bovine Herpes Virus 1 in Yaks (Bos grunniens) from the Qinghai-Tibetan Plateau in China: A Meta-analysis

Prevalence of Bovine Herpes Virus 1 in Yaks (Bos grunniens) from the Qinghai-Tibetan Plateau in China: A Meta-analysis

Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease

Sequence dependencies and biophysical features both govern cleavage of diverse cut‐sites by HIV protease

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