Little is known about the requirements for human T-cell leukemia virus type I (HTLV-I) entry, including the identity of the cellular receptor(s). Recently, we have generated an HTLV-I surface glycoprotein (SU) immu-noadhesin, HTSU-IgG, which binds specifically to cell-surface protein(s) critical for HTLV-I-mediated entry in cell lines. Here, expression of the HTLV-I SU binding protein on primary cells of the immune system was examined. The immu-noadhesin specifically bound to adult T cells, B cells, NK cells, and macrophages. Cell stimulation dramatically increased the amount of binding, with the highest levels of binding on CD4 and CD8 T cells. Naive (CD45RA high , CD62L high) CD4 T cells derived from cord blood cells, in contrast to other primary cells and all cell lines examined, bound no detectable HTLV-I SU. However, following stimulation , the level of HTSU-IgG binding was rapidly induced (fewer than 6 hours), reaching the level of binding seen on adult CD4 T cells by 72 hours. In contrast to HTLV-I virions, the soluble HTSU-IgG did not effect T-cell activation or proliferation. When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction, HTSU-IgG inhibited proliferation at less than 1 ng/ mL. These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immuno-biology of CD4 T cells. (Blood. 2003;101: 3085-3092)

Little is known about the requirements for human T-cell leukemia virus type 1 (HTLV-1) entry, including the identity of the cellular receptor(s).Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus which is the etiological agent of a severe lymphocyte neoplasia called adult T-cell leukemia/lymphoma (ATL) (53, 77) and a progressive neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (19,48). The virus is endemic in southern Japan, the Caribbean basin, Central and South America, and portions of West Africa. HTLV-1 and the closely related human T-cell leukemia virus type 2 (HTLV-2) are uncommon in the general populations of the United States and Europe. However, one recent study revealed that HTLV is prevalent in the United States among paid blood donors, African-American health care clinic patients, Amerindians, intravenous drug users, and patients with other-than-low-grade non-Hodgkin's lymphoma (52).ATL is a malignancy of CD4 ϩ T cells. It has been generally believed that the majority of the cells infected by HTLV-1 in vivo are CD4 ϩ T cells (30, 54). However, HTLV-1 can infect all subsets of human lymphocytes in vitro, and recent studies indicate that both CD4 ϩ and CD8 ϩ T cells serve as viral reservoirs in HTLV-1-associated myelopathy/tropical spastic paraparesis patients (42). Although capable of infecting a number of different cell types, HTLV-1 is poorly infectious in both primary cells and established cell lines in vitro.As for all retroviruses, entry of HTLV-1 into target cells is mediated by the envelope glycoproteins (Env), a surface glycoprotein (SU), and a transmembrane glycoprotein (TM). The HTLV-1 Env proteins are initially synthesized as precursor proteins, which are subsequently glycosylated and cleaved in the Golgi apparatus by a furin-like cellular protease to yield the SU (gp46) and the TM (gp21) glycoproteins. Following cleavage, the SU and the TM remain associated with each other through noncovalent interactions (51). As for other retroviruses, it is believed that the HTLV-1 SU glycoprotein specifically binds to a cellular receptor, inducing a conformational change in the SU-TM complex. This change activates a fusion domain within TM, allowing fusion of the viral and cellular membranes (5,9,10,37,51,55,56). Recent work using HTLV/ murine leukemia virus (MLV) envelope chimeras strongly suggests that the region of SU that interacts with the receptor is located within the N-terminal two-thirds of the protein (29). For HTLV-1, both SU and TM appear to play an additional role in a postfusion event critical for infectivity (11,28).The cellular receptor(s) for HTLV-1 have not yet been identified. Based on results from receptor interference assays, HTLV-1 is believed to share a common receptor with HTLV-2 and other primate T-cell leukemia/lymphoma viruses (64, 55). The gene encoding the receptor was mapped to chromosome 17 and further localized to 17q23. 2-25.3 (18, 35, 55), although later studies have questioned this assignment (27,47,67).A number of diffe...