APOBEC3G Generates Nonsense Mutations in HTLV-1 Proviral Genomes In Vivo.
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) induces cell proliferation after infection, leading to efficient transmission by cell-to-cell contact. After a long latent period, a fraction of carriers develop adult T-cell leukemia (ATL). In ATL cells, genetic changes in the tax gene were reported in about 10% of ATL cases. To determine genetic changes that may occur throughout the provirus, we determined the whole sequences of HTLV-1 provirus in 60 ATL cases. Abortive genetic changes including deletion, insertion and nonsense mutations were frequent in all viral genes except in the HBZ gene, which is transcribed from the minus strand of the virus. G-to-A base substitutions were the most frequent mutations in ATL cells. Sequence context of G-to-A mutations was in accordance with the preferred target sequence of human APOBEC3G (hA3G). Target sequences of hA3G were less frequent in the plus strand of the HBZ coding region than in other coding regions of HTLV-1 provirus. Nonsense mutations in viral genes including tax were also observed in proviruses from asymptomatic carriers, indicating that these mutations were generated during reverse transcription and prior to oncogenesis. That hA3G targets the minus strand during reverse transcription explains why the HBZ gene, which is encoded by the plus strand of provirus, is not susceptible to such nonsense mutations. HTLV-1 infected cells likely take advantage of hA3G to escape from the host immune system by losing expression of viral proteins.
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