?(Fig.1A1A). The HTLV-1 p12I protein localizes to lipid rafts. p12I may have evolved to minimize immune recognition of infected CD4+ T cells, to impair the function of infected cytotoxic CD8+ T cells, and to favor viral persistence in the infected host. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes a rare, aggressive hematopoietic malignancy of mature T cells, designated adult T-cell leukemia/lymphoma, as well as a progressive myelopathy defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (18, 20, 25, 42, 55). HTLV-1 infects human CD4+ and CD8+ (22, 33, 35, 39, 43) T cells of memory phenotype and is believed to confer a proliferative and survival advantage on infected memory T-cell clones, with consequent accumulation of Vesnarinone somatic mutations and neoplastic transformation (16). The provirus is thought to be mostly latent, mainly in resting T cells (21). However, once T cells are stimulated by antigen, the proviral DNA can be expressed, endangering the survival of the infected cells because of immune recognition. The HTLV-1 genome, in addition to structural (Gag and Env) and enzymatic (Pol) proteins, encodes positive regulators of viral expression from open reading frames (ORFs) III and IV, such as Tax and Rex, as well as two negative regulators, p30II (ORF II) (40) and HBZ, which is encoded from the minus strand RNA (19). ORF I encodes a 12-kDa protein (p12I) that in cells is localized in the endoplasmic reticulum (ER)/Golgi (13, 28, 32). The p12I protein has been shown to have multiple functions. p12I interacts with the interleukin-2 receptor (IL-2R) and Vesnarinone c chains, increases STAT-5 activation, and decreases the threshold of the IL-2 requirement for T-cell proliferation (38, 41) in primary human lymphocytes. In the ER/Golgi, p12I binds both the IL-2 receptor chains and the major histocompatibility complex (MHC) class I heavy chain and interferes with their trafficking to the cell surface (28, 38). p12I also binds to calreticulin and calnexin (13) and increases calcium release and nuclear factor of activated T cells (NFAT) activation upon phorbol myristate acetate (PMA) stimulation of T cells. This effect bypasses antigen receptor ligation, as it also occurs in linker for activation of T cells (LAT)-deficient T cells (1, 12, 29). T-cell receptor (TCR) signaling occurs through a cascade of events (51, 52) that involve activation of the protein tyrosine kinases Lck and Fyn, which phosphorylate the tyrosines in the cytosolic domains of TCR and the CD3 subunits. These phosphorylated domains become the docking sites for ZAP70, which is phosphorylated and activated when bound. Activated ZAP70 phosphorylates LAT, which then binds Grb2, phospholipase C-1 (PLC-1), and the p85 subunit of phosphatidylinositol 3-kinase and, indirectly, Vav, Cb1, and SLP76. The recruitment of these critical molecules to Vesnarinone the membrane ultimately results in multiple events, including calcium release, dephosphorylation and nuclear translocation of NFAT, enhancement of transcription, cytokine production, and T-cell proliferation. These events lead over time to protein and lipid rearrangements that occur during the formation of the immunological synapse between the T Vesnarinone cell and the antigen-presenting cells (APCs) (7, 37). These membrane rearrangements include effects on the lipid rafts, a heterogeneous mixture of components on the surfaces of cells that includes the glycosphingolipid- and cholesterol-rich microdomains and proteins that are enriched in these regions (46). The function of immune synapse formation and the various molecular sorting events that accompany it are controversial but may include effects on signaling and down-regulation of various molecules (5, 48). TCR stimulation of Mouse monoclonal to PRKDC HTLV-1-infected T cells and IL-2 production could be deleterious to viral persistence, as the viral transactivator, Tax, increases viral expression by exploiting CREB/ATF that is activated by IL-2 (50). Thus, viral expression is likely maintained at a very low level in vivo to minimize the elimination of.