title: PA28γ is a novel corepressor of HTLV-1 replication and controls viral latency.
abstract: The establishment of a latent reservoir by human tumor viruses is a vital step in initiating cellular transformation and represents a major shortcoming to current therapeutic strategies and the ability to eradicate virus-infected cells. Human T-cell leukemia virus type 1 (HTLV-1) establishes a lifelong infection and is linked to adult T-cell leukemia lymphoma (ATLL). Here, we demonstrate that HTLV-1 p30 recruits the cellular proteasome activator PA28γ onto the viral tax/rex mRNA to prevent its nuclear export and suppress virus replication. Interaction of p30 with a PA28γ retaining fully functional proteasome activity is required for p30's ability to repress HTLV-1. Consistently, HTLV-1 molecular clones replicate better and produce more virus particles in PA28γ-deficient cells. These results define a unique and novel role for the cellular factor PA28γ in the control of nuclear RNA trafficking and HTLV-1–induced latency. Importantly, knockdown of PA28γ expression in ATLL cells latently infected with HTLV-1 reactivates expression of viral tax/rex RNA and the Tax protein. Because Tax is the most immunogenic viral antigen and triggers strong CTL responses, our results suggest that PA28γ-targeted therapy may reactivate virus expression from latently infected cells and allow their eradication from the host.
  
  
  CONCLUSIONS
  PA28γ acts as a co-repressor of HTLV-1 p30 to suppress virus replication and is required for the maintenance of viral latency. HTLV-1 has evolved a unique function mediated by its posttranscriptional repressor p30, which is not found in HTLV-2.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Nga Ling
authors.initials: NL
authors.lastname: Ko
authors.forename: John M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Marcia
authors.initials: M
authors.lastname: Bellon
authors.forename: Xue Tao
authors.initials: XT
authors.lastname: Bai
authors.forename: Sergey P
authors.initials: SP
authors.lastname: Shevtsov
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dundr
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001693:Biological Transport, Active / Q000235:genetics; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016370:Gene Products, rex / Q000235:genetics / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D001324:Autoantigens; D016370:Gene Products, rex; D016356:Gene Products, tax; C099558:Ki antigen; D012367:RNA, Viral; C514844:rex Protein, Human T-lymphotropic virus 1; C514970:tax protein, Human T-lymphotrophic virus 1; D046988:Proteasome Endopeptidase Complex