The human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia/lymphoma as well as tropical spastic paraparesis/ HTLV-1-associated myelopathy. HTLV-1 is transmitted to T cells through the virological synapse and by extracellular viral assemblies. Here, we uncovered an additional mechanism of virus transmission that is regulated by the HTLV-1-encoded p8 protein. We found that the p8 protein, known to anergize T cells, is also able to increase T-cell contact through lymphocyte function-associated antigen-1 clustering. In addition, p8 augments the number and length of cellular conduits among T cells and is transferred to neighboring T cells through these conduits. p8, by establishing a T-cell network, enhances the envelope-dependent transmission of HTLV-1. Thus, the ability of p8 to simultaneously anergize and cluster T cells, together with its induction of cellular conduits, secures virus propagation while avoiding the host's immune surveillance. This work identifies p8 as a viral target for the development of therapeutic strategies that may limit the expansion of infected cells in HTLV-1 carriers and decrease HTLV-1-associated morbidity.human leukemia retrovirus | orf-I

The identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wildtype genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species. (Blood. 2010;116(19):3809-3817)

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99-amino acid hydrophobic membrane protein, p12(I), that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12(I). The removal of a noncanonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12(I) is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8-kDa protein. The 8-kDa protein in turn traffics to the cell surface, is recruited to the immunologic synapse following T-cell receptor (TCR) ligation, and down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12(I) resides in the ER and interacts with the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals predominant amino acid substitutions within ORF-I that affect proteolytic cleavage, suggesting that ER-associated functions of p12(I) may contribute to the survival and proliferation of the infected T cells in the host.

A pproximately 2 to 3% of human T cell leukemia virus type 1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma (ATL) and another 2 to 3% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) in their lifetimes (1-4). In addition to HAM/TSP (5, 6), HTLV-1 is also associated with other inflammatory conditions, such as uveitis (6) Sjögren's syndrome (7), bronchoalveolitis and arthritis (8), and polymyositis (9). It is noteworthy that some patients present with more than one of these inflammatory conditions (10). HTLV-1 primarily infects CD4 ϩ and CD8 ϩ effector and memory T cells and regulatory CD4 ϩ CD25 ϩ T cells (11,12). A high viral DNA burden in peripheral blood mononuclear cells (PBMCs) is a risk factor for HAM/TSP (13) and ATL development (14-16), and patients with HAM/TSP have a higher virus level in the cerebrospinal fluid (CSF) than in the peripheral blood (12). The virus level alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including the host immune response (16)(17)(18)(19)(20). HAM/TSP patients present diverse immunological alterations, such as increased levels of spontaneous lymphocyte proliferation (21, 22), tax-specific cytotoxic CD8 ϩ T cell expansion, and the production of high levels of inflammatory cytokines (23)(24)(25). Several studies have also suggested that monocytes are involved in immune reg-