Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation.
Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is dispensable for HTLV-1-mediated cellular transformation in cell culture, but is required for efficient viral infectivity and persistence in rabbits. In most adult T-cell leukemia (ATL) cells, Tax oncoprotein expression is typically low or undetectable, whereas Hbz gene expression is maintained, suggesting that Hbz expression may support infected cell survival and, ultimately, leukemogenesis. Emerging data indicate that HBZ protein can interact with cAMP response element binding protein (CREB) and Jun family members, altering transcription factor binding and transactivation of both viral and cellular promoters. Herein, lentiviral vectors that express Hbz-specific short hairpin (sh)-RNA effectively decreased both Hbz mRNA and HBZ protein expression in transduced HTLV-1-transformed SLB-1 T cells. Hbz knockdown correlated with a significant decrease in T-cell proliferation in culture. Both SLB-1 and SLB-1-Hbz knockdown cells engrafted into inoculated NOD/SCID(gammachain-/-) mice to form solid tumors that also infiltrated multiple tissues. However, tumor formation and organ infiltration were significantly decreased in animals challenged with SLB-1-Hbz knockdown cells. Our data indicate that Hbz expression enhances the proliferative capacity of HTLV-1-infected T cells, playing a critical role in cell survival and ultimately HTLV-1 tumorigenesis in the infected host.
Arnold
Joshua
J
Center for Retrovirus Research, Department of Veterinary Biosciences and Molecular Virology Immunology, The Ohio State University, Columbus, OH 43210, USA.
Zimmerman
Bevin
B
Li
Min
M
Lairmore
Michael D
MD
Green
Patrick L
PL
D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002472:Cell Transformation, Viral; D016373:DNA, Antisense / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005814:Genes, Viral; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012191:Retroviridae Proteins; D013601:T-Lymphocytes / Q000473:pathology* / Q000821:virology*; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; D016373:DNA, Antisense; D004279:DNA, Viral; C479751:HBZ protein, human T-cell leukemia virus type I; D012333:RNA, Messenger; D012367:RNA, Viral; D012191:Retroviridae Proteins; D014764:Viral Proteins