Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex.
Human T lymphotropic virus type I (HTLV-I) infection is largely latent in infected persons. How HTLV-1 establishes latency and reactivates is unclear. Here we show that most HTLV-1-infected HeLa cells become senescent. By contrast, when NF-κB activity is blocked, senescence is averted, and infected cells continue to divide and chronically produce viral proteins. A small population of infected NF-κB-normal HeLa cells expresses low but detectable levels of Tax and Rex, albeit not Gag or Env. In these "latently" infected cells, HTLV-1 LTR trans-activation by Tax persists, but NF-κB trans-activation is attenuated due to inhibition by HBZ, the HTLV-1 antisense protein. Furthermore, Gag-Pol mRNA localizes primarily in the nuclei of these cells. Importantly, HBZ was found to inhibit Rex-mediated export of intron-containing mRNAs. Over-expression of Rex or shRNA-mediated silencing of HBZ led to viral reactivation. Importantly, strong NF-κB inhibition also reactivates HTLV-1. Hence, during HTLV-1 infection, when Tax/Rex expression is robust and dominant over HBZ, productive infection ensues with expression of structural proteins and NF-κB hyper-activation, which induces senescence. When Tax/Rex expression is muted and HBZ is dominant, latent infection is established with expression of regulatory (Tax/Rex/HBZ) but not structural proteins. HBZ maintains viral latency by down-regulating Tax-induced NF-κB activation and senescence, and by inhibiting Rex-mediated expression of viral structural proteins.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Subha
S
Philip
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Muhammad Atif
MA
Zahoor
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Huijun
H
Zhi
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Yik-Khuan
YK
Ho
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Chou-Zen
CZ
Giam
D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D016370:Gene Products, rex / Q000235:genetics / Q000378:metabolism*; D016356:Gene Products, tax; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D012191:Retroviridae Proteins; D015533:Transcriptional Activation / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology*
D050976:Basic-Leucine Zipper Transcription Factors; D016370:Gene Products, rex; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012367:RNA, Viral; D012191:Retroviridae Proteins; D014764:Viral Proteins; C514844:rex Protein, Human T-lymphotropic virus 1; C514970:tax protein, Human T-lymphotrophic virus 1