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...
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Public Library of Science (PLoS)
2014-04-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004040&type=printable |
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| author | Subha Philip Muhammad Atif Zahoor Huijun Zhi Yik-Khuan Ho Chou-Zen Giam |
| author_facet | Subha Philip Muhammad Atif Zahoor Huijun Zhi Yik-Khuan Ho Chou-Zen Giam |
| author_sort | Subha Philip |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-71fc9f9be94742d08bfeff7bd00a76fe |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-71fc9f9be94742d08bfeff7bd00a76fe2025-08-20T03:00:25ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-04-01104e100404010.1371/journal.ppat.1004040Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex.Subha PhilipMuhammad Atif ZahoorHuijun ZhiYik-Khuan HoChou-Zen GiamHuman 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004040&type=printable |
| spellingShingle | Subha Philip Muhammad Atif Zahoor Huijun Zhi Yik-Khuan Ho Chou-Zen Giam Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. PLoS Pathogens |
| title | Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. |
| title_full | Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. |
| title_fullStr | Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. |
| title_full_unstemmed | Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. |
| title_short | Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. |
| title_sort | regulation of human t lymphotropic virus type i latency and reactivation by hbz and rex |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004040&type=printable |
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