title: A novel therapeutic molecule against HTLV-1 infection targeting provirus.
abstract: Human T-cell leukemia virus type 1 (HTLV-1), which causes adult T-cell leukemia (ATL) in humans, establishes a life-long latent infection. Current therapies are not very effective against HTLV-1-associated disorders. A novel therapeutic approach may help to combat HTLV-1 infection. A molecular therapy that targets the proviral genome is favorable because the therapeutic effect occurs specifically in HTLV-1-infected cells, regardless of whether they express viral genes. In this proof-of-concept study, we developed a therapeutic molecule based on zinc finger nuclease (ZFN) to achieve this goal. We designed a ZFN that specifically recognized conserved region of HTLV-1 long terminal repeat (LTR) and introduced it into various HTLV-1-positive human T-cell lines, including HTLV-1-transformed and ATL-derived cell lines. The ZFN disrupted the promoter function of HTLV-1 LTR and specifically killed HTLV-1-infected cells. We also showed a potential approach of this therapeutic molecule to remove the proviral genome from HTLV-1-infected cells, something that has not been possible before. The therapeutic effect of ZFN was confirmed in an in vivo model of ATL. This strategy may form the basis of a therapy that can eradicate HTLV-1 infection. Similar approaches can be used to target other malignancy-associated viruses.
authors: Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors: A
authors: A
authors: Tanaka
authors: S
authors: S
authors: Takeda
authors: R
authors: R
authors: Kariya
authors: K
authors: K
authors: Matsuda
authors: E
authors: E
authors: Urano
authors: S
authors: S
authors: Okada
authors: J
authors: J
authors: Komano
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D023061:Gene Order; D017930:Genes, Reporter; D005822:Genetic Vectors; D015490:HTLV-I Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011533:Proviruses / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000235:genetics; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D016335:Zinc Fingers
chemical_list: D004720:Endonucleases