Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Human T-lymphotropic virus type I-mediated lymphocyte immortalization: viral replication and lymphoproliferation.
Diss Abstr Int [B]; 55(2):289 1994. Unique Identifier : AIDSLINE ICDB/95607438 Kimata JT; Washington Univ.
Abstract:
Infection of T-cells by human T-lymphotropic virus type I (HTLV-I) is associated with aberrant immune activation. The activation state may play a central role in the development of adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I associated myelopathy. Therefore, understanding how HTLV-I deregulates T-cell proliferative responses is of fundamental interest. An interleukin 2(IL2)/IL2 receptor (IL2R) autocrine growth loop trans activated by the viral regulatory protein Tax was proposed to be the mechanism underlying aberrant T-cell proliferative responses. We tested the hypothesis by examining viral and cellular gene expression during the course of primary human lymphocyte infection and immortalization by HTLV-I in vitro. In infected cell cultures, high expression of the early regulatory gene transcript, pX (tax-rex mRNA), was favored at a stage when normal lymphocytes stop proliferating, suggesting its importance in deregulating lymphocyte proliferation and the transformation process. IL2 was found to be the major proliferation inducing factor. Interestingly, IL2 expression was transient, and the levels of IL2 and IL2R mRNA expression were temporally dissociated from the level of pX mRNA expression. This suggested that IL2-mediated proliferation did not result from Tax trans activation of the IL2 gene. In contrast, we discovered that direct contact between virus expressing T cells and uninfected T cells induced IL2 activity and T-cell proliferation. Infection by HTLV-I was not a prerequisite. Using antibody neutralizing experiments, we identified a requirement for the cellular glycoprotein CD58, its receptor (CD2), and the T-cell receptor/CD3 complex in HTLV-I-induced T-cell activation by cell to cell contact. Antibodies to viral proteins were non-neutralizing. Importantly, this work establishes a role for cell adhesion/ signalling molecules in HTLV-I-mediated lymphocyte activation and disease. Finally, we devised a method for constructing full length molecular clones of HTLV-I. This marked the first time that proviral clones could be propagated stably in plasmid vectors. Through transfection experiments, we demonstrated that the clones produced virus particles. Unexpectedly, expression was permissive in fibroblast cell lines but restricted in lymphoid cell lines. These proviral clones should be useful in future investigations aimed at understanding the regulation of HTLV-I gene expression, viral assembly, and pathogenicity of HTLV-I. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-17581)
Keywords: Cell Division Cell Line, Transformed *Cell Transformation, Viral Human *HTLV-I/PHYSIOLOGY Interleukin-2/GENETICS/PHYSIOLOGY Receptors, Interleukin-2/GENETICS/PHYSIOLOGY RNA, Messenger/GENETICS/METABOLISM *Virus Replication THESIS 950530
M9551040
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
