SELECTIVE INFECTION OF HUMAN T-LYMPHOTROPIC VIRUS TYPE-1 (HTLV-1)-INFECTED CELLS BY CHIMERIC HUMAN IMMUNODEFICIENCY VIRUSES CONTAINING HTLV-1 TAX RESPONSE ELEMENTS IN THE LONG TERMINAL REPEAT

Previous studies have suggested that the human immunodeficiency virus long terminal repeat (HIV LTR) enhancer/promoter sequences contribute to the replication ability of HIV in different T-cell lines; mutation of these sequences can alter HIV tropism. We have utilized site-specif ic mutagenesis to generate variants of HIV that exhibit specific tropi sm for human T-lymphotropic virus type 1 (HTLV-1) Tax-expressing CD4() T cells, The wild-type HIV LTR NF-kappa B and Sp1 sites in an infect ious molecular clone of HIV type 1 were replaced with sequences derive d from the 21-bp Tax response elements (TRE) from the HTLV-1 LTR to ge nerate TRE-containing chimeric HIVs (TRE-HIVs). The TRE-HIVs exhibit s elective replication and cell killing in HTLV-infected human CD4(+) T cells, but not in HTLV-negative T cells, Transient transfections sugge sted that Tax-TRE interactions could account for the observed replicat ion specificity, The TRE containing HIV LTRs were synergistically acti vated by the HIV Tat and HTLV-1 Tax transactivators. These results dem onstrate that it is possible to specifically target HIV replication an d cytotoxicity to HTLV-1(+), CD4(+) human T cells, on the basis of Tax -TRE interactions, and provide a model for the development of specific , cytotoxic, retroviral gene therapy vectors for HTLV-l-infected cells based on alterations of the LTR transcriptional regulatory elements, They also suggest that HIV Tat can cooperate with heterologous transcr iptional activators, such as Tax, which act through upstream binding s ites without directly binding to DNA.