Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) persists despite a vigorous virus-specific host immune response, and causes adult T-cell leukemia and lymphoma in approximately 2% of infected individuals. Here we report that HTLV-1 has evolved a genetic function to restrict its own replication by a novel post-transcriptional mechanism. The HTLV-1-encoded p30(II) is a nuclear-resident protein that binds to, and retains in the nucleus, the doubly spliced mRNA encoding the Tax and Rex proteins. Because Tex and Rex are positive regulators of viral gene expression, their inhibition by p30(II) reduces virion production. p30(II) inhibits virus expression by reducing Tax and Rex protein expression.

Human T-cell leukemia virus type 1 (HTLV-1) establishes a persistent infection in the host despite a vigorous virus-specific immune response. Here we demonstrate that an HTLV-1-encoded protein, p12 I , resides in the endoplasmic reticulum (ER) and Golgi and physically binds to the free human major histocompatibility complex class I heavy chains (MHC-I-Hc) encoded by the HLA-A2, -B7, and -Cw4 alleles. As a result of this interaction, the newly synthesized MHC-I-Hc fails to associate with ␤ 2 -microglobulin and is retrotranslocated to the cytosol, where it is degraded by the proteasome complex. Targeting of the free MHC-I-Hc, and not the MHC-I-Hc-␤ 2 -microglobulin complex, by p12 I represents a novel mechanism of viral interference and disrupts the intracellular trafficking of MHC-I, which results in a significant decrease in surface levels of MHC-I on human T-cells. These findings suggest that the interaction of p12 I with MHC-1-Hc may interfere with antigen presentation in vivo and facilitate escape of HTLV-1-infected cells from immune recognition.

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...

Three protein isoforms are encoded by the human T-cell leukemia/lymphotropic virus type I pX region open reading frames (ORF) I and II through alternative splicing. Both the singly and doubly spliced mRNAs from ORF I encode a single 12-kDa protein (p121), whereas two distinct proteins of 13 kDa (p13"I) and 30 kDa (p30"1) are encoded from the ORF II alternatively spliced mRNA. Because the p12' protein is very hydrophobic and poorly immunogenic, we genetically engineered its cDNA by adding a short stretch of amino acids from the highly immunogenic epitope HAl1 of influenza virus or the AUl epitope of bovine papillomavirus. The HAl epitope was also added to the p13", and p30"1 proteins, albeit rabbit immune sera raised against synthetic peptides were also available. To determine in which cellular compartments these proteins reside, we transfected the tagged and wild-type cDNAs in HeLa/Tat cells and studied their localization by indirect immunofluorescence. The p12' protein was identified in the cellular endomembranes and, particularly, in the perinuclear area. p13" and p30"1 were found in the nuclei and nucleoli of the transfected cells, respectively. The presence of the HAl epitope at the carboxy terminus of p13I" and p30"1 did not interfere with their cellular localization,