The human leukaemia virus HTLV-1 causes chronic inflammatory disease or an aggressive T-cell malignancy in about 10% of infected people. The risk of these diseases is strongly correlated with the proviral load, which frequently exceeds 10% of peripheral blood mononuclear cells. The high proviral load is limited by a strong, chronically activated host immune response. HTLV-1 does not release cell-free virions, but propagates both within and between hosts by cell-to-cell contact, via the virological synapse.
Until recently, HTLV-1 was thought to be latent in vivo, and persisted chiefly by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells. However, we have shown that a typical individual carries between 104 and 105 clones, and the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. We recently discovered that HTLV-1 alters host chromatin structure in the infected cell, by binding the chromatin architectural protein CTCF, which regulates higher-order chromatin structure and gene expression in vertebrates. Thus, HTLV-1 does a remarkable experiment of nature, by changing the conformation of chromatin in tens of thousands of different ways in each infected host. Two broad questions are raised: first, how does CTCF benefit the virus? Second, how does the change in chromatin structure affect the host? I will show that the abnormal chromatin looping caused by CTCF can deregulate host gene expression and so may act as an oncogenic driver. I will also present evidence that HTLV-1 plus-strand is expressed in intense, intermittent bursts, and that expression minus strand is not, as is currently believed, constitutive.