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Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining
Published on: December 23, 2016
Rhesus monkey TRIM5α SPRY domain recognizes multiple epitopes that span several capsid monomers on the surface of the
Nikolaos Biris1, Andrei Tomashevski, Akash Bhattacharya
1Department of Biochemistry and Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Abstract:
The restriction factor TRIM5α binds to the capsid protein of the retroviral core and blocks retroviral replication. The affinity of TRIM5α for the capsid is a major host tropism determinant of HIV and other primate immunodeficiency viruses, but the molecular interface involved in this host-pathogen interaction remains poorly characterized. Here we use NMR spectroscopy to investigate binding of the rhesus TRIM5α SPRY domain to a selection of HIV capsid constructs. The data are consistent with a model in which one SPRY domain interacts with more than one capsid monomer within the assembled retroviral core. The highly mobile SPRY v1 loop appears to span the gap between neighboring capsid hexamers making interhexamer contacts critical for restriction. The interaction interface is extensive, involves mobile loops and multiple epitopes, and lacks interaction hot spots. These properties, which may enhance resistance of TRIM5α to capsid mutations, result in relatively low affinity of the individual SPRY domains for the capsid, and the TRIM5α-mediated restriction depends on the avidity effect arising from the oligomerization of TRIM5α.
Insights
The restriction factor TRIM5α binds to retroviral capsids, blocking replication. Its SPRY domain uses mobile loops for extensive capsid interaction, with multimerization driving restriction efficacy.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- The restriction factor TRIM5α inhibits retroviral replication by binding to the viral capsid.
- Understanding the TRIM5α-capsid interaction is crucial for HIV tropism and host-pathogen dynamics.
- The precise molecular interface of this interaction remains poorly defined.
Purpose of the Study:
- To investigate the binding interface between the rhesus TRIM5α SPRY domain and HIV capsid constructs.
- To elucidate the structural basis of TRIM5α's restriction of retroviral replication.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study the binding interactions.
- Analysis focused on the interaction between the rhesus TRIM5α SPRY domain and HIV capsid fragments.
Main Results:
- NMR data suggest one TRIM5α SPRY domain interacts with multiple capsid monomers within the assembled core.
- A mobile SPRY v1 loop appears to mediate inter-hexamer contacts critical for restriction.
- The interaction interface is extensive, involving mobile loops and multiple epitopes, lacking specific hot spots.
Conclusions:
- TRIM5α's extensive, low-affinity interactions with capsid monomers, driven by avidity from oligomerization, contribute to retroviral restriction.
- This binding mechanism may confer resistance to capsid mutations, enhancing TRIM5α's effectiveness.
- The findings provide molecular insights into TRIM5α-mediated host defense against primate lentiviruses.
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