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...

Replication-competent herpes simplex virus (HSV-1) mutants are used in clinical trials in the experimental treatment of cancer. Mutants G207, HSV1716, NV1020, and Oncovex GM-CSF share in common a defect in one or both copies of the gene encoding the neurovirulence factor, ICP34.5, and are thus neuroattenuated. These viruses are acknowledged to differ from one another (a) in the specific types of mutations intentionally introduced during their derivation and (b) in the inherent genetic differences retained from the different parent strains used in their construction. Unintended mutations are expected to emerge at some low frequency during the selection for and passage of mutant viruses. Here we demonstrate that during the construction of the oncolytic virus R3616, a nonsense mutation arose in an untargeted region of the HSV-1 genome that resulted in a substantial truncation of the viral protein known as UL3. This report is the first published documentation that oncolytic herpesviruses developed and used in clinical trials contain adventitious mutations. The implications of these findings for the characterization and development of vectors proposed for use in clinical trials are discussed.

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