Human retroviral latency: regulation and dynamics at the single-cell level

Latent persistence of retroviruses, including HIV-1 and the human leukaemia virus HTLV-1, remains a major barrier to their eradication from the host. HTLV-1 appears to be latent in circulating lymphocytes, but the strong, persistently activated immune response indicates that the virus is not latent in vivo. We infer that HTLV-1 undergoes intermittent bursts of gene expression. We have now obtained direct evidence of HTLV-1 gene bursts in naturally-infected cells in vitro. The central question “What regulates HTLV-1 latency?” therefore becomes “What regulates the gene expression bursts of HTLV-1?” We have developed a powerful set of materials and techniques to identify the causes and quantify the kinetics of this gene bursting at the single-cell level. A major regulator of mammalian gene expression is the key chromatin architectural protein CTCF. We recently discovered that the HTLV-1 provirus binds CTCF and alters the higher-order structure of host chromatin. In this programme we will investigate the consequences for both the virus and the host cell of this remarkable experiment of nature. The results of this work will answer fundamental questions on the persistence and pathogenesis of HTLV-1, and contribute to the growing understanding of mammalian gene bursting.