Abstract SY23-03: How does HTLV-1 cause leukemia

Abstract

Abstract The retrovirus human T-lymphotropic virus type 1 (HTLV-1) causes an aggressive, rapidly fatal malignancy of CD4+ T cells, called adult T-cell leukemia/lymphoma (ATL), in 5% of infected individuals. Recent evidence on the clonal diversity and molecular virology of HTLV-1 and on the host genetic and immune response is changing the understanding of oncogenesis in HTLV-1 infection. It was previously believed that HTLV-1 was latent in vivo and persisted by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells, and that this oligoclonal proliferation predisposed to the malignancy ATL. However, we have shown that a typical individual carries between 104 and 105 clones and that the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. The central challenge remains to explain the regulation of HTLV-1 latency in vivo and the role of the host immune response in determining the set-point proviral load and the risk of ATL. I propose here three hypotheses. First, that ATL results from the accumulation of replicative mutations in HTLV-1-infected T-cell clones that persist for decades, typically over 40 years. Second, that the quality of the host immune response, chiefly the CTL response, determines the size and clonal diversity of the HTLV-1 reservoir, the net proliferation rate of HTLV-1-infected T cells, and therefore the risk of ATL. Third, that abnormal chromatin looping in the host genome caused by HTLV-1 can deregulate host gene expression and so contribute to the risk of ATL. Citation Format: Charles Bangham. How does HTLV-1 cause leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY23-03. doi:10.1158/1538-7445.AM2017-SY23-03