Human T-cell leukemia virus

Human T-cell leukemia virus: Description, Causes and Risk Factors: A group of viruses (genus BLTV-HTLV retroviruses, family Retroviridae) that are lymphotropic with a selective affinity for the helper/inducer cell subset of T lymphocytes and that are associated with adult T-cell leukemia and tropical spastic paraparesis. The human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with two fatal human diseases: adult T-cell leukemia (ATL) and the Neurodegenerative disease tropical spastic paraparesis/human T-cell leukemia virus -1-associated myelopathy. ATL is an aggressive lymphoproliferative disease which can be classified into distinct clinical subtypes: pre-ATL, the acute form, the sub-acute or smoldering form, the chronic form, and ATL lymphoma. HTLV-1 is endemic in areas of Southern Japan, the Caribbean basin, inter-tropical Africa, the Middle East, South America, and Papua New Guinea. It is estimated that 20-30 million people worldwide may be infected with human T-cell leukemia virus -1. Of those, about 4% will go on to develop disease after a latency of 20 or more years. In vivo, HTLV-1 infects CD4+ peripheral T cells, but has also been detected, to a lesser extent, in CD8+ T cells. Unlike typical transforming retroviruses, HTLV-1 does not encode a cellular oncogene or disrupt cellular gene regulation by insertional mutagenesis. While several viral proteins act in concert to allow infected cells to avoid immune regulation, modulate anti- and pro-apoptotic signals, and increase T-cell responsiveness to extracellular stimuli, the viral Tax protein is the major viral oncoprotein. Human T-cell leukemia virus HTLV-1 is a complex delta-retrovirus whose genome encodes structural and enzymatic proteins: Gag, Env, reverse transcriptase, protease, and integrase. In addition, HTLV-1 has a region at the 3' end of the virus, called pX, which encodes four partially overlapping reading frames (ORFs). These ORFs code for regulatory proteins which impact the expression and replication of the virus. Arguably the most frequently detected alteration in human cancer is inactivation of the tumor suppressor, p53. In fact, mutation of p53 is associated with approximately 50% of all human cancers. In addition, p53 is a frequent target for inactivation by viral transforming proteins such as SV40 large T-antigen, HPV E6, hepatitis B X-antigen, and adenovirus E1A and E1B. The p53 protein belongs to a family of related proteins that includes two other members, p63 and p73. While the proteins are all structurally and functionally related, p63 and p73 have clear roles in development, whereas p53 seems to have evolved to   prevent tumor development and has earned the name "cellular gatekeeper." Symptoms: Signs and symptoms of HTLV myelopathy include: Motor and sensory changes in the extremities.
  • Spastic gait in combination with weakness of the lower limbs.
  • Clonus.
  • (neurogenic bladder) and bladder cancer.
Other neurologic findings that may be found in HTLV include: Mild cognitive impairment. Diagnosis: No gold standard exists for diagnosis of HTLV infection. The aim was to compare the accuracy of a combination of two sensitive ELISAs with Western blot (WB), a line immunoassay, and PCR for diagnosis of HTLV infection. Treatment: Because adult T-cell leukemia/lymphoma is such a rare disease, finding enough patients to enroll in clinical trials is difficult. However, several new drugs being studied in clinical trials for other T-cell lymphomas are emerging as potential treatments for HTLV-1, including: PDX (pralatrexate).
  • Vorinostat (Zolinza).
  • Lenalidomide (Revlimid).
  • Bortezomib (Velcade™).
The role of using allogeneic stem cell transplant (high-dose chemotherapy followed by donor cell transplantation) is also being evaluated as a promising treatment for HTLV-1 patients who have relapsed. Advances in the treatment of HTLV were brought about by allogeneic bone marrow or stem cell transplantation. Absence of graft-versus-host disease (GVHD) was linked with relapse of ATL, suggesting that GVHD or graft-versus-ATL may be implicated in the clinical effects of allogeneic stem cell transplantation. Furthermore, 16 patients with ATL, who were over 50 years of age, were treated with allogeneic stem cell transplantation with reduced conditioning intensity (radioimmunosorbent test [RIST]) from HLA-matched sibling donors. Among 9 patients in whom ATL relapsed after transplantation, 3 achieved a second complete remission after rapid discontinuation of cyclosporin A/cyclosporine A. This finding strongly suggests the presence of a graft-versus-ATL effect in these patients. In addition, Tax peptide-recognizing cells were detected by a tetramer assay in patients after allogeneic stem cell transplantation. In 8 patients, the provirus became undetectable by real-time PCR. Among these, 2 patients who received grafts from HTLV-I-positive donors also became provirus-negative by real-time PCR after radioimmunosorbent test. Since the provirus load is relatively constant in HTLV-I-infected individuals, this finding indicates an enhanced immune response against human T-cell leukemia virus -I after RIST, which suppresses the provirus load. This may account for the effectiveness of allogeneic stem cell transplantation to ATL. However, Tax expression is frequently lost in ATL cells as described above. Many questions arise, such as whether the tax gene status is correlated with the effect of allogeneic stem cell transplantation, and whether the effectiveness of the anti-HTLV-I immune response is against leukemic cells or non-leukemic HTLV-I-infected cells. Nevertheless, these data suggest that potentiation of the immune response against viral proteins such as Tax may be an attractive way to treat ATL patients. Such strategies may enable preventive treatment of high-risk HTLV-I carriers, such as those with familial ATL history, predisposing genetic factors to ATL, a higher provirus load, etc. NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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