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.