The interferon response inhibits HIV particle production by induction of TRIM22.
Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated genes. We confirmed, as in previous studies, that TRIM22 over-expression inhibited HIV replication. To assess the role of TRIM22 expressed under natural inducing conditions, we compared the effects of interferon in cells depleted for TRIM22 using RNAi and found that HIV particle release was significantly increased in the knockdown, implying that TRIM22 acts as a natural antiviral effector. Further studies showed that TRIM22 inhibited budding of virus-like particles containing Gag only, indicating that Gag was the target of TRIM22. TRIM22 did not block the release of MLV or EIAV Gag particles. Inhibition was associated with diffuse cytoplasmic staining of HIV Gag rather than accumulation at the plasma membrane, suggesting TRIM22 disrupts proper trafficking. Mutational analyses of TRIM22 showed that the catalytic amino acids Cys15 and Cys18 of the RING domain are required for TRIM22 antiviral activity. These data disclose a pathway by which Type 1 interferons obstruct HIV replication.
Barr
Stephen D
SD
Department of Medical Microbiology and Immunology, University of Alberta, Alberta Institute for Viral Immunology, Edmonton, Alberta, Canada. stephen.barr@ualberta.ca
Smiley
James R
JR
Bushman
Frederic D
FD
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane; D004252:DNA Mutational Analysis; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D015778:Minor Histocompatibility Antigens; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000070584:Tripartite Motif Proteins; D015854:Up-Regulation; D014771:Virion / Q000187:drug effects* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D015683:Gene Products, gag; D054298:Human Immunodeficiency Virus Proteins; D007370:Interferon Type I; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C094314:TRIM22 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins