An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation

Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2016-07, Vol.353 (6298), p.506-508
Main Authors: Schur, Florian K. M., Obr, Martin, Hagen, Wim J. H., Wan, William, Jakobi, Arjen J., Kirkpatrick, Joanna M., Sachse, Carsten, Kräusslich, Hans-Georg, Briggs, John A. G.
Format: Article
Language:English
Subjects:
Amino acids
Antiviral Agents - pharmacology
Assembly
Atomic structure
Capsid - chemistry
Cleavage
Cryoelectron Microscopy
Drug Resistance, Viral - genetics
gag Gene Products, Human Immunodeficiency Virus - chemistry
gag Gene Products, Human Immunodeficiency Virus - genetics
HIV
HIV-1 - drug effects
HIV-1 - genetics
HIV-1 - physiology
Human immunodeficiency virus
Lentivirus
Maturation
Models, Chemical
Molecular biology
Mutation
Networks
Peptides
Peptides - chemistry
Protein Conformation
Proteins
Proteolysis
Tomography
Virus Assembly
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Summary:Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is the key regulator of assembly and maturation and is the target of MIs. We applied optimized cryo-electron tomography and subtomogram averaging to resolve this region within assembled immature HIV-1 particles at 3.9 angstrom resolution and built an atomic model. The structure reveals a network of intra- and intermolecular interactions mediating immature HIV-1 assembly. The proteolytic cleavage site between CA and SP1 is inaccessible to protease. We suggest that MIs prevent CA-SP1 cleavage by stabilizing the structure, and MI resistance develops by destabilizing CA-SP1.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaf9620