title: Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation.
abstract: The matrix (MA) domain of HIV Gag has important functions in directing the trafficking of Gag to sites of assembly and mediating the incorporation of the envelope glycoprotein (Env) into assembling particles. HIV-1 MA has been shown to form trimers in vitro; however, neither the presence nor the role of MA trimers has been documented in HIV-1 virions. We developed a cross-linking strategy to reveal MA trimers in virions of replication-competent HIV-1. By mutagenesis of trimer interface residues, we demonstrated a correlation between loss of MA trimerization and loss of Env incorporation. Additionally, we found that truncating the long cytoplasmic tail of Env restores incorporation of Env into MA trimer-defective particles, thus rescuing infectivity. We therefore propose a model whereby MA trimerization is required to form a lattice capable of accommodating the long cytoplasmic tail of HIV-1 Env; in the absence of MA trimerization, Env is sterically excluded from the assembling particle. These findings establish MA trimerization as an obligatory step in the assembly of infectious HIV-1 virions. As such, the MA trimer interface may represent a novel drug target for the development of antiretrovirals.
authors.affiliation: Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201.
authors.forename: Philip R
authors.identifier: http://orcid.org/0000-0001-8151-4967
authors.initials: PR
authors.lastname: Tedbury
authors.affiliation: Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201.
authors.forename: Mariia
authors.initials: M
authors.lastname: Novikova
authors.affiliation: Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201.
authors.forename: Sherimay D
authors.initials: SD
authors.lastname: Ablan
authors.affiliation: Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201 efreed@nih.gov.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
mesh_terms: D003432:Cross-Linking Reagents / Q000494:pharmacology; D004220:Disulfides / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000235:genetics; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D014763:Viral Matrix Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; D013912:Threonine
keywords: HIV; envelope; matrix; retrovirus; trimerization