The Pathogenesis Of Htlvassociated Tcell Lymphoma And Leukemia

Unlike other oncornaviruses, the BLV/PTLV have not been shown to transduce cellular oncogenes, or rely on insertional mutagenesis (i.e., promoter or enhancer insertion) to transform infected cells. Instead, they induce oncogenesis in a manner more similar to the DNA tumor viruses (e.g., papillomaviruses, adenovirus, SV-40) in that viral regulatory proteins interact with host mechanisms to result in deregulation of the normal cell cycle constraints. The viral protein Tax, in addition to trans-activating viral RNA transcription, has been shown, in vitro, to trans-activate a number of cellular genes, among them potent T-cell growth factors and antiapoptotic factors. Tax can also act as a trans-suppressor by competing with host transcription factors for necessary DNA-binding proteins. Tax has also been shown to promote cellular mutations by inhibiting base excision repair.44 HTLV-infected cells also upregulate the expression of ATL-derived factor (ADF), a human homologue to Escherichia coli thioredoxin, which has the ability to act as an autocrine growth factor, activate host transcription factors, and protect against apoptosis, all by modulating the redox state of the cell.

Activation of protooncogenes by Tax and ADF would promote cell cycle progression in infected cells and, ultimately, transformation. Protection from apoptosis stimulated by these same factors would allow infected cells to elude immune surveillance and protect against DNA damage mediated apoptosis triggered by the accumulation of cellular mutations. These mutations could contribute to tumorogenesis if they activate protooncogenes or deactivate tumor suppressor genes. The trans-activation of cellular genes also accounts for many of the paraneoplastic conditions associated with HTLV-1.

Development of HTLV-associated adult T-cell lymphoma/ leukemia (ATL) is seemingly controlled by the infected individual's genetic predisposition. If the individual can mount a strong antiviral CTL response, his or her immune system will eliminate cells as they are being transformed, putting that individual at low risk for developing ATL, but increasing the risk for autoimmune diseases that have also been associated with HTLV. Those who cannot mount such a strong CTL response to the virus will not clear transformed cells with the same efficiency, and are therefore at a much greater risk of developing ATL.

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