Molecular cloning of human T-cell leukaemia virus type I (HTLV-I) proteins and the role of HTLV-I infection in multiple drug resistance (MDR)

To facilitate the structural and functional analysis of Human T-cell leukaemia virus type-I (HTLV-I) a recombinant proviral expression system was to be employed in which viral protein expression is uncoupled from the inefficient process of infection. Several molecular genomic HTLV-I proviral clones were isolated and used to express viral proteins. However, none of these molecular HTLV-I proviral clones were found to be fully competent for virus expression and did not allow the further development of the expression system. HTLV-I is etiologically linked to a rapidly progressing T-cell malignancy known as adult T-cell leukaemia (ATL) and a degenerative neurological disorder called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). These diseases are noted for their poor response and high resistance to chemotherapy. Clinical drug resistance has been associated with the overexpression of the mdr-1 gene and its protein product P-glycoprotein (PGP). The presence of multiple drug resistant (MDR) cell phenotypes in peripheral blood mononuclear cells (PMBC) from HTLV-I infected patients was assessed and enchanced mdr-1 mRNA expression and PGP drug efflux activity was observed. MDR phenotypes were found in nine out of ten HTLV-I infected subjects tested. Development of MDR was independent of disease type or status with significant MDR activity being found in ATL, lymphoma type ATL, TSP/HAM and asymptomatic individuals. Furthermore the demonstration of stimulation and trans-activation of the mdr-1 gene suggests potential molecular mechanisms for the development of drug resistant cell phenotypes induced by HTLV-I infection.