Reduction of human T‐cell leukemia virus type‐1 infection in mice lacking nuclear factor‐κB‐inducing kinase

Human T‐cell lymphotropic virus type 1 (HTLV‐1) causes adult T‐cell leukemia and inflammatory disorders. Aberrant activation of nuclear factor‐κB (NF‐κB) has been linked to HTLV‐1 pathogenesis and to various kinds of cancers, including adult T‐cell leukemia. NF‐κB‐inducing kinase (NIK) is critical for non‐canonical activation of NF‐κB and for the development of lymphoid organs. HTLV‐1 activates NF‐κB by the non‐canonical pathway, but examination of the role of NIK in proliferation of HTLV‐1‐infected cells in vivo has been hindered by lack of a suitable animal model. Alymphoplasia (aly/aly) mice bear a mutation of NIK, resulting in defects in the development of lymphoid organs and severe deficiencies in both humoral and cell‐mediated immunity. In the present study we therefore used a mouse model of HTLV‐1 infection with aly/aly mice. The number of HTLV‐1‐infected cells in the reservoir organs in aly/aly mice was significantly smaller than in the control group 1 month after infection. In addition, aly/aly mice did not maintain provirus for 1 year and antibodies against HTLV‐1 were undetectable. These results demonstrate that the absence of functional NIK impairs primary HTLV‐1 proliferation and abolishes the maintenance of provirus. Interestingly, clonal proliferation of HTLV‐1‐infected mouse cells was not detected in aly/aly mice, which is consistent with the lack of HTLV‐1 persistence. These observations imply that the clonal proliferation of HTLV‐1‐infected cells in secondary lymphoid organs might be important for HTLV‐1 persistence. (Cancer Sci 2008; 99: 872–878)