Hypoxia and HIF-1α promote lytic de novo KSHV infection
The impact of different stress conditions on the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) primary infection that can occur in vivo remains largely unknown. We hypothesized that KSHV can establish a latency or lytic cycle following de novo infection, depending on the conditions o...
Elmentve itt :
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| Dokumentumtípus: | Cikk |
| Megjelent: |
2023
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| Sorozat: | JOURNAL OF VIROLOGY
97 No. 11 |
| Tárgyszavak: | |
| doi: | 10.1128/jvi.00972-23 |
| mtmt: | 34402081 |
| Online Access: | http://publicatio.bibl.u-szeged.hu/29083 |
| Tartalmi kivonat: | The impact of different stress conditions on the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) primary infection that can occur in vivo remains largely unknown. We hypothesized that KSHV can establish a latency or lytic cycle following de novo infection, depending on the conditions of the cellular environment. Previous studies showed that hypoxia is a natural stress condition that promotes lytic reactivation and contributes to KSHV pathogenesis, but its effect on de novo KSHV infection is unknown. To test the effect of hypoxia on KSHV infection, we infected cells under normoxia and hypoxia, performed a comparative analysis of viral gene expression and viral replication, and tested chromatinization of the KSHV genome during infection. We found that hypoxia induces viral lytic gene expression and viral replication following de novo infection in several biologically relevant cell types, in which the virus normally establishes latency under normoxia. We also found that hypoxia reduces the level of repressive heterochromatin and promotes the formation of a transcriptionally permissive chromatin on the incoming viral DNA during infection. We demonstrate that silencing hypoxia-inducible factor-1 alpha (HIF-1 alpha) during hypoxia abrogates lytic KSHV infection, while the overexpression of HIF-1 alpha under normoxia is sufficient to drive lytic KSHV infection. Also, we determined that the DNA-binding domain and the N-terminal but not the C-terminal transactivation domain of HIF-1 alpha are required for HIF-1 alpha-induced lytic gene expression. Altogether, our data indicate that HIF-1 alpha accumulation, which can be induced by hypoxia, prevents the establishment of latency and promotes lytic KSHV infection following primary infection. |
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| Terjedelem/Fizikai jellemzők: | 18 |
| ISSN: | 0022-538X |