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Updated: May 28, 2026
10:50
Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
Identification and structural characterization of novel genetic elements in the HIV-1 V3 loop regulating coreceptor
Valentina Svicher1, Claudia Alteri, Anna Artese
1Department of Experimental Medicine and Biochemical Sciences, University of 'Tor Vergata', Rome, Italy.
Antiviral Therapy
|October 26, 2011
Summary
New HIV-1 V3 genetic determinants were identified that impact gp120 binding to CCR5. These findings refine understanding of HIV tropism and inform the development of CCR5 antagonists for better clinical efficacy.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- The interaction between HIV-1 gp120 and the CCR5 N-terminus is crucial for R5-tropic virus entry.
- This interaction influences the effectiveness of CCR5 antagonists.
- Limited knowledge exists on how gp120 V3 domain genetic variations affect this interaction strength.
Purpose of the Study:
- To identify novel genetic determinants within the HIV-1 gp120 V3 domain that correlate with coreceptor usage.
- To investigate how these V3 genetic determinants modulate the binding affinity of gp120 to the CCR5 N-terminus.
- To provide insights for improving CCR5 antagonist efficacy and designing new entry inhibitors.
Main Methods:
- Assessed HIV-1 coreceptor usage in 251 patients using enhanced-sensitivity Trofile assay and V3 sequencing.
- Employed Geno2pheno algorithm for tropism prediction.
- Utilized Bayesian partitional and recursive model selection to define V3 genetic determinants.
- Evaluated gp120-CCR5 N-terminus interaction via docking and molecular dynamics simulations.
Main Results:
- Identified specific V3 genetic determinants (N5Y, N7K, A19V) significantly correlating with CCR5/CXCR4 usage beyond known positions.
- These determinants were found in a subset of CXCR4-using viruses (N5Y: 4.5%, N7K: 6%) and CCR5-using viruses (A19V: 2.6%).
- N5Y, N7K, and A19V mutations decreased gp120 affinity for CCR5 N-terminus, with N7K significantly disrupting the interaction between V3 position 7 and CCR5 position 14.
Conclusions:
- Key V3 sequence determinants influencing HIV tropism were identified and structurally/phenotypically confirmed.
- This knowledge allows for more precise tuning of CCR5 antagonist efficacy in clinical settings.
- Findings offer molecular insights for the rational design of novel HIV entry inhibitors.
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