Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15.
The goal of this study was to elucidate the molecular mechanism by which type I IFN inhibits assembly and release of HIV-1 virions. Our study revealed that the IFN-induced ubiquitin-like protein ISG15 mimics the IFN effect and inhibits release of HIV-1 virions without having any effect on the synthesis of HIV-1 proteins in the cells. ISG15 expression specifically inhibited ubiquitination of Gag and Tsg101 and disrupted the interaction of the Gag L domain with Tsg101, but conjugation of ISG15 to Gag or Tsg101 was not detected. The inhibition of Gag-Tsg101 interaction was also detected in HIV-1 infected, IFN-treated cells. Elimination of ISG15 expression by small interfering RNA reversed the IFN-mediated inhibition of HIV-1 replication and release of virions. These results indicated a critical role for ISG15 in the IFN-mediated inhibition of late stages of HIV-1 assembly and release and pointed to a mechanism by which the innate antiviral response targets the cellular endosomal trafficking pathway used by HIV-1 to exit the cell. Identification of ISG15 as the critical component in IFN-mediated inhibition of HIV-1 release advances the understanding of the IFN-mediated inhibition of HIV-1 replication and uncovers a target for the anti HIV-1 therapy.
Okumura
Atsushi
A
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA.
Lu
Gengshi
G
Pitha-Rowe
Ian
I
Pitha
Paula M
PM
D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism; D005822:Genetic Vectors; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D016086:Lentivirus / Q000235:genetics; D015233:Models, Statistical; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism / Q000502:physiology; D014779:Virus Replication; D000099177:Tsg101 Protein
D000998:Antiviral Agents; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015683:Gene Products, gag; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025801:Ubiquitin; D014452:Ubiquitins; D000099177:Tsg101 Protein; C074034:ISG15 protein, human