The p12 I protein, encoded by the pX open reading frame I of the human T-lymphotropic virus type 1 (HTLV-1), is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p12 I contains 4 minimal proline-rich, src homology 3-binding motifs (PXXP), a characteristic commonly found in proteins involved in signaling pathways, it has not been known whether p12 I has a role in modulating intracellular signaling pathways. This study demonstrated that p12 I binds to the cytoplasmic domain of the interleukin-2 receptor (IL-2R)  chain that is involved in the recruitment of the Jak1 and Jak3 kinases. As a result of this interaction, p12 I IntroductionHuman T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), 1 and its genome carries genetic information for the structural and enzymatic proteins, the regulatory proteins Tax and Rex, and other open reading frames (orfs) encoding small proteins with largely unknown functions. 2-5 HTLV-1 infects and immortalizes primary human T cells in vitro, and after several months, these cells acquire the ability to grow in the absence of interleukin-2 (IL-2). 1 The switch to IL-2 independence correlates in most cases with acquisition of a constitutive activation of the Jak/signal transducers and activators of transcription (STAT) pathway 6-8 and decreased expression of the src homology 2-containing tyrosine phosphatase 1 protein, 9 which regulates signaling from several hematopoietic surface receptors. 10 HTLV-1 also confers longevity on T cells in vivo, since expansion of T cells with identical integrations for HTLV-1 can be found at several-year intervals in the same infected individuals. 11 These findings raise the question of how CD4 ϩ T cells carrying the HTLV-1 provirus can expand and survive for a long time in vivo.The HTLV-1 p12 I protein, a hydrophobic protein resident in the endoplasmic reticulum (ER) and Golgi 58 that is encoded by the 3Ј end orf I of the viral genome, 12 forms dimers, 13 has weak oncogenic properties, and binds to the p16 subunit of the vacuolar hydrogen adenosine diphosphatase (H ϩ ATPase). 14 Expression of p12 I in infected cells is suggested by the presence of transcripts in cultured 3,5,15 and ex vivo cells from individuals infected with HTLV-1. 5 The orf I is likely expressed in vivo because antibodies (Abs) and cytotoxic T lymphocytes to peptides from the orf I protein have been detected. 16,17 Importantly, ablation of the splice acceptor site for the singly spliced p12 I messenger RNA from a molecular clone of HTLV-1 impaired viral infectivity in a rabbit model in vivo. 18 This may be partly related to the finding that p12 I interferes with major histocompatibility complex class I (MHC I) heavy-chain trafficking and may facilitate escape of HTLV-1-infected cells from the host's immune surveillance. 58 We previously reported that p12 I also binds the IL-2 receptor (IL-2R)  and ␥ c chains and affects their expression on the cell surface. 19 IL-2 is an essential cytokine for the growth and s...
The FDC group had noninferior efficacy over 48 weeks to the SE group in treatment-experienced subjects with VF.
A two-stage, cyclic fed-batch fermentation process to produce recombinant human lymphokine was designed. The organism used in the study was Escherichia coli K-12 containing a temperature-sensitive walkaway plasmid bearing an insert which codes for a human lymphokine. Transcription of the recombinant gene is controlled by a lambda repressor/pL promoter system. The lambda promoter is regulated by the temperature-sensitive product of the cl857 gene at 30 degrees C, but at 42 degrees C the promoter is derepressed. The first or growth, stage of the process was maintained at 28 degrees C and operated in the fed-batch mode. The vessel was fed at a rate which gives a constant specific growth rate using a media designed to maintain a constant optical density OD(600) of 50. After the volume in the first stage reached the maximum working volume of the vessel (12 L), a portion of the vessel contents was transferred to the second stage. The second, or induction/product formation, stage also operated in the fed-batch mode, was kept at 42 degrees C, and was fed with a media that is conducive to recombinant human lymphokine synthesis. An optical density of more than 100 was consistently achieved in the second stage. Thirty cycles were completed with a consistent yield of human lymphokine and cell density in each cycle. The process was used to produce 200 L of OD(600) 50 material from the first stage in 10 days. The volumetric productivity (g lymphokine/L. day) of the two-stage, cyclic fed-batch process is twice that of a single-stage, fed-batch fermentation process.
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