Identification and structural characterization of novel genetic elements in the HIV-1 V3 loop regulating coreceptor usage

Valentina Svicher, Claudia Alteri, Anna Artese, Jing Maria Zhang, Giosuè Costa, Fabio Mercurio, Roberta D'Arrigo, Stefano Alcaro, Giorgio Palù, Massimo Clementi, Maurizio Zazzi, Massimo Andreoni, Andrea Antinori, Adriano Lazzarin, Francesca Ceccherini-Silberstein, Carlo Federico Perno

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: The interaction between HIV-1 gp120 and CCR5 N terminus is critical for R5-virus entry and affects CCR5 antagonists' activity. Knowledge of how different genetic signatures of gp120 V3 domain effect the strength of this interaction is limited. Methods: HIV-1 coreceptor usage was assessed in 251 patients using enhanced-sensitivity Trofile assay and V3 sequencing plus tropism prediction by Geno2pheno algorithm. Bayesian partitional model and recursive model selection have been used to define V3 genetic determinants correlated with different coreceptor usage. Gp120 interaction with CCR5 N terminus was evaluated by docking-analysis/molecular-dynamic simulations starting from the model described previously. Results: Selected V3 genetic determinants (beyond known aminoacidic positions) significantly correlate with CCR5-or CXCR4-usage, and modulate gp120 affinity for CCR5 N terminus. This is the case for N5Y and N7K, absent in CCR5-using viruses and present in 4.5% and 6% of CXCR4-using viruses, respectively, and A19V, occurring in 2.6% of CCR5-using viruses and 22.0% of CXCR4-using viruses (P=10 -2 to 10 -7). Their presence determines a decreased affinity for CCR5 N terminus even stronger than that observed in the presence of the well-known mutation S11R (N5Y: -6.60 Kcal/mol; N7K: -5.40 Kcal/mol; A19V: -5.60 Kcal/mol; S11R: -6.70 Kcal/mol; WT: -6.90 Kcal/mol). N7K significantly increases the distance between V3 position 7 and sulphotyrosine at CCR5 position 14 (crucial for binding to gp120; from 4.22 Å to 8.30 Å), thus abrogating the interaction between these two important residues. Conclusions: Key determinants for tropism within the V3 sequence, confirmed by structure- and by phenotypictropism, have been identified. This information can be used for a finer tuning of potential efficacy of CCR5-antagonists in clinical practice, and to provide molecular implications for design of new entry inhibitors.

Original languageEnglish
Pages (from-to)1035-1045
Number of pages11
JournalAntiviral Therapy
Volume16
Issue number7
DOIs
Publication statusPublished - 2011

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HIV-1
Viruses
Tropism
Virus Internalization
Molecular Dynamics Simulation
Mutation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Identification and structural characterization of novel genetic elements in the HIV-1 V3 loop regulating coreceptor usage. / Svicher, Valentina; Alteri, Claudia; Artese, Anna; Zhang, Jing Maria; Costa, Giosuè; Mercurio, Fabio; D'Arrigo, Roberta; Alcaro, Stefano; Palù, Giorgio; Clementi, Massimo; Zazzi, Maurizio; Andreoni, Massimo; Antinori, Andrea; Lazzarin, Adriano; Ceccherini-Silberstein, Francesca; Perno, Carlo Federico.

In: Antiviral Therapy, Vol. 16, No. 7, 2011, p. 1035-1045.

Research output: Contribution to journalArticle

Svicher, V, Alteri, C, Artese, A, Zhang, JM, Costa, G, Mercurio, F, D'Arrigo, R, Alcaro, S, Palù, G, Clementi, M, Zazzi, M, Andreoni, M, Antinori, A, Lazzarin, A, Ceccherini-Silberstein, F & Perno, CF 2011, 'Identification and structural characterization of novel genetic elements in the HIV-1 V3 loop regulating coreceptor usage', Antiviral Therapy, vol. 16, no. 7, pp. 1035-1045. https://doi.org/10.3851/IMP1862
Svicher, Valentina ; Alteri, Claudia ; Artese, Anna ; Zhang, Jing Maria ; Costa, Giosuè ; Mercurio, Fabio ; D'Arrigo, Roberta ; Alcaro, Stefano ; Palù, Giorgio ; Clementi, Massimo ; Zazzi, Maurizio ; Andreoni, Massimo ; Antinori, Andrea ; Lazzarin, Adriano ; Ceccherini-Silberstein, Francesca ; Perno, Carlo Federico. / Identification and structural characterization of novel genetic elements in the HIV-1 V3 loop regulating coreceptor usage. In: Antiviral Therapy. 2011 ; Vol. 16, No. 7. pp. 1035-1045.
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AU - Alteri, Claudia

AU - Artese, Anna

AU - Zhang, Jing Maria

AU - Costa, Giosuè

AU - Mercurio, Fabio

AU - D'Arrigo, Roberta

AU - Alcaro, Stefano

AU - Palù, Giorgio

AU - Clementi, Massimo

AU - Zazzi, Maurizio

AU - Andreoni, Massimo

AU - Antinori, Andrea

AU - Lazzarin, Adriano

AU - Ceccherini-Silberstein, Francesca

AU - Perno, Carlo Federico

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N2 - Background: The interaction between HIV-1 gp120 and CCR5 N terminus is critical for R5-virus entry and affects CCR5 antagonists' activity. Knowledge of how different genetic signatures of gp120 V3 domain effect the strength of this interaction is limited. Methods: HIV-1 coreceptor usage was assessed in 251 patients using enhanced-sensitivity Trofile assay and V3 sequencing plus tropism prediction by Geno2pheno algorithm. Bayesian partitional model and recursive model selection have been used to define V3 genetic determinants correlated with different coreceptor usage. Gp120 interaction with CCR5 N terminus was evaluated by docking-analysis/molecular-dynamic simulations starting from the model described previously. Results: Selected V3 genetic determinants (beyond known aminoacidic positions) significantly correlate with CCR5-or CXCR4-usage, and modulate gp120 affinity for CCR5 N terminus. This is the case for N5Y and N7K, absent in CCR5-using viruses and present in 4.5% and 6% of CXCR4-using viruses, respectively, and A19V, occurring in 2.6% of CCR5-using viruses and 22.0% of CXCR4-using viruses (P=10 -2 to 10 -7). Their presence determines a decreased affinity for CCR5 N terminus even stronger than that observed in the presence of the well-known mutation S11R (N5Y: -6.60 Kcal/mol; N7K: -5.40 Kcal/mol; A19V: -5.60 Kcal/mol; S11R: -6.70 Kcal/mol; WT: -6.90 Kcal/mol). N7K significantly increases the distance between V3 position 7 and sulphotyrosine at CCR5 position 14 (crucial for binding to gp120; from 4.22 Å to 8.30 Å), thus abrogating the interaction between these two important residues. Conclusions: Key determinants for tropism within the V3 sequence, confirmed by structure- and by phenotypictropism, have been identified. This information can be used for a finer tuning of potential efficacy of CCR5-antagonists in clinical practice, and to provide molecular implications for design of new entry inhibitors.

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