HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP

Human T-lymphotropic virus type 1 (HTLV-1) causes leukaemia or chronic inflammatory disease in ∼5% of infected hosts. The level of proviral expression of HTLV-1 differs significantly among infected people, even at the same proviral load (proportion of infected mononuclear cells in the circulation). A high level of expression of the HTLV-1 provirus is associated with a high proviral load and a high risk of the inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). But the factors that control the rate of HTLV-1 proviral expression remain unknown. Here we show that proviral integration sites of HTLV-1 in vivo are not randomly distributed within the human genome but are associated with transcriptionally active regions. Comparison of proviral integration sites between individuals with high and low levels of proviral expression, and between provirus-expressing and provirus non-expressing cells from within an individual, demonstrated that frequent integration into transcription units was associated with an increased rate of proviral expression. An increased frequency of integration sites in transcription units in individuals with high proviral expression was also associated with the inflammatory disease HAM/TSP. By comparing the distribution of integration sites in human lymphocytes infected in short-term cell culture with those from persistent infection in vivo, we infer the action of two selective forces that shape the distribution of integration sites in vivo: positive selection for cells containing proviral integration sites in transcriptionally active regions of the genome, and negative selection against cells with proviral integration sites within transcription units.Author Summary: The human leukaemia virus HTLV-1 causes a lifelong infection that cannot be cleared by the immune system. By integrating into the host's DNA, the virus can lie dormant within the cell. The virus can then be reactivated, by processes that are only partly understood, causing the infected cell to multiply and leading to an increase in the quantity of virus in the infected person. In some infected people, the virus is reactivated much faster than in others, and such people are more likely to develop HTLV-1-associated inflammatory diseases such as HAM/TSP, which results in paralysis of the legs. It is not understood what determines this rate of viral reactivation in each person. In this study, we found that integration of HTLV-1 in the host's DNA close to other genes was associated with faster viral reactivation and a higher probability of HAM/TSP. By comparing the viral integration site positions in samples from patients and in cells infected with HTLV-1 in the laboratory, we can identify some of the major forces that allow the virus to persist lifelong whilst avoiding eradication by the immune response.