HTLV gene regulation: because size matters, transcription is not enough

Despite being discovered in animals in the early 20th century, the scientific interest in retroviruses was boosted with the discovery of human retroviruses (human T-leukemia/lymphoma virus [HTLV] and HIV), which are responsible for significant morbidity and mortality. HTLV was identified more than 25 years ago as the etiological agent of adult T-cell leukemia/lymphoma. It was then shown to be a complex retrovirus, given that it not only encodes the characteristic retroviral Gag, Pol and Env proteins, but also regulatory and accessory proteins. Since the first studies documenting the role of these proteins in viral expression, the picture has become increasingly more complex. Indeed, owing to the limited size of its genome that contains overlapping open-reading frames, HTLV has evolved unique ways to regulate its expression. Retroviral expression was originally thought to be mainly controlled through the regulation of transcription from the 5 long-terminal repeats, but we now know that the 3 long-terminal repeats also serve as promoters. Regulation of splicing and mRNA export, and post-translational modifications of viral protein also play a major role. This review discusses the latest insights gained into the field of HTLV gene expression.