HTLV-1 latency by a viral-encoded protein that blocks Tax and Rex production

Christophe Nicot,* Miroslav Dundr,† Julie M. Johnson,* Jake R. Fullen,* Risaku Fukumoto,* Tom Misteli,† Genoveffa Franchini*

National Cancer Institute, Bethesda, Maryland (USA)

Background: Human retroviruses such as HTLV-1/2 and HIV-1/2 integrate in the cell genome and are eliminated only when cells die, despite the vigorous virus-specific response that the host mounts against viral proteins. These observations raise questions about viral strategies for persistence and immune evasion. Retroviral genomes are silenced by a variety of mechanisms: methylation of proviral DNA, defects in the cellular milieu of transcription factors, accumulation of genetic defects in regulatory or structural proteins. In retroviruses, however, active viral products that regulate latency have not been described. Results: Here we report the first evidence of an active gene function in the HTLV-1 genome that causes latency. The HTLV-1 p30^II protein binds to and retains in the nucleus the mRNA for the two positive regulators of viral expression, the Tax and Rex proteins. Transduction of p30^II by lentivirus vectors in HTLV-1-infected T-cells is associated with viral production, suggesting a role for the protein in latency. Lastly, the HTLV-1 p30^II protein also decreases HTLV-2 production, indicating that HTLV-2 has likely evolved a similar function. Conclusions: HTLV-1/2, DNA viruses, have evolved a specific genetic function that causes latency.