title: TRIM22 inhibits HIV-1 transcription independently of its E3 ubiquitin ligase activity, Tat, and NF-kappaB-responsive long terminal repeat elements.
abstract: Previous studies identified clones of the U937 promonocytic cell line that were either permissive or nonpermissive for human immunodeficiency virus type 1 (HIV-1) replication. These clones were investigated further in the search for host restriction factors that could explain their differential capacity to support HIV-1 replication. Among known HIV-1 restriction factors screened, tripartite motif-containing protein 22 (TRIM22) was the only factor constitutively expressed in nonpermissive and absent in permissive U937 cells. Stable TRIM22 knockdown (KD) rescued HIV-1 long-terminal-repeat (LTR)-driven transcription in KD-nonpermissive cells to the levels observed in permissive cells. Conversely, transduction-mediated expression of TRIM22 in permissive cells reduced LTR-driven luciferase expression by ∼7-fold, supporting a negative role of TRIM22 in HIV-1 transcription. This finding was further confirmed in the human T cell line A3.01 expressing TRIM22. Moreover, overexpression of TRIM22 in 293T cells significantly impaired basal and phorbol myristate acetate-ionomycin-induced HIV-1 LTR-driven gene expression, whereas inhibition of tumor necrosis factor alpha-induced viral transcription was a consequence of lower basal expression. In agreement, TRIM22 equally inhibited an LTR construct lacking the tandem NF-κB binding sites. In addition, TRIM22 did not affect Tat-mediated LTR transactivation. Finally, these effects were independent of TRIM22 E3 ubiquitin-ligase activity. In the context of replication-competent virus, significantly higher levels of HIV-1 production were observed in KD-nonpermissive versus control nonpermissive U937 cells after infection. In contrast, lower peak levels of HIV-1 replication characterized U937 and A3.01 cells expressing TRIM22 versus their control transduced counterpart. Thus, nuclear TRIM22 significantly impairs HIV-1 replication, likely by interfering with Tat- and NF-κB-independent LTR-driven transcription.
authors.affiliation: Viral Pathogens and Biosafety Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. kajaste.anna@hsr.it
authors.forename: Anna
authors.initials: A
authors.lastname: Kajaste-Rudnitski
authors.forename: Sara S
authors.initials: SS
authors.lastname: Marelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pultrone
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.forename: Pradeep D
authors.initials: PD
authors.lastname: Uchil
authors.forename: Nadir
authors.initials: N
authors.lastname: Mechti
authors.forename: Walther
authors.initials: W
authors.lastname: Mothes
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
authors.forename: Jeremy
authors.initials: J
authors.lastname: Luban
authors.forename: Elisa
authors.initials: E
authors.lastname: Vicenzi
mesh_terms: D002460:Cell Line; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009000:Monocytes / Q000276:immunology / Q000821:virology; D012097:Repressor Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D014779:Virus Replication
chemical_list: D015778:Minor Histocompatibility Antigens; D012097:Repressor Proteins; C094314:TRIM22 protein, human; D000070584:Tripartite Motif Proteins