Abstract
HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy of in vitro assembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30' from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of an N-terminal domain interface (NDI) pocket that is amenable to antiviral targeting.IMPORTANCE Precise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30' of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.
Highlights
HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle
We explored sites in capsid that differ between pentameric and hexameric environments to identify novel targets for the design of inhibitors that interfere with proper assembly of the HIV-1 core
Two atomic models of the entire capsid core are available in the Protein Data Bank (PDB) archive (PDB identifiers [ID]: 3J3Q and 3J3Y) [31]
Summary
HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, none of the currently identified compounds are used in the clinic for treatment of HIV infection. Reverse transcription occurs in the core and is tightly coupled to the poorly understood process of capsid core disassembly, or uncoating [5,6,7,8,9,10] These events lead to the importation of the double-stranded viral DNA into the host cell nucleus, where it is integrated into the host DNA
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