Role of accessory proteins of HTLV-1 in viral replication, T cell activation, and cellular gene expression

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1), causes adult T cell leukemia/lymphoma (ATLL), and initiates a variety of immune mediated disorders. The viral genome encodes common structural and enzymatic proteins characteristic of all retroviruses and utilizes alternative splicing and alternate codon usage to make several regulatory and accessory proteins encoded in the pX region (pX ORF I to IV). Recent studies indicate that the accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORF I and II, contribute to viral replication and the ability of the virus to maintain typical in vivo expression levels. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. These HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes suggesting a role for the calcineurin-binding protein p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I activates NFAT, a key T cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30II localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related co-activators of transcription. The mitochondrial localizing p13II induces morphologic changes in the organelle and may influence energy metabolism infected cells. Future studies of the molecular details HTLV-1 "accessory" proteins interactions will provide important new directions for investigations of HTLV-1 and related viruses associated with lymphoproliferative diseases. Thus, the accessory proteins of HTLV-1, once thought to be dispensable for viral replication, have proven to be directly involved in viral spread in vivo and represent potential targets for therapeutic intervention against HTLV-1 infection and disease.

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

“…The ability of HTLV-1 to produce these regulatory and accessory proteins through alternative splicing and selective codon usage classifies the virus among the complex retroviruses (4,23). Recent studies have indicated a significant role for HTLV-1 accessory proteins in the life cycle of HTLV-1, particularly during the early phase of the viral infection of lymphocytes (1,9,16,27,30,32,40). Less is known, however, about the accessory protein p13 II , a singly spliced product of the second open reading frame (ORF II) of the pX gene region.…”

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 II Is Required for Viral Infectivity In Vivo

“…The HTLV-1 genome consists of long terminal repeats; genes encoding the structural and enzymatic proteins Gag, Pol, and Env; and a pX region located between env and the 3Ј long terminal repeat that encodes the regulatory proteins Tax and Rex, as well as several nonstructural "accessory" proteins, p12 II (12,16,28,30). HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATL), a highly aggressive T-cell malignancy (reviewed in reference 43).…”

International Retrovirology Association brings together scientists and clinicians to bridge discoveries about human T-lymphotropic viruses from the laboratory to clinical trials

“…Data continue to emerge linking HTLV-1 infection with some impairment of immune function that manifests as a reduced ability to clear, despite therapy infections, certain infections such as Strongyloides stercoralis, Schistosomiasis species, and Sarcoptes scabiei. Recent studies have provided important new roles for the non-structural viral proteins of HTLVs e.g., p12 I , p13 II , and p30 II , which continue to provide important clues into virus replication and T-lymphocyte activation [13-15]. The continued discovery of new, but related members of the deltaretrovirus family of viruses raised intriguing questions regarding the origin and transmission of human retroviruses.…”