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-specific mutagenesis to generate variants of HIV that exhibit specific tropism 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 infectious molecular clone of HIV type 1 were replaced with sequences derived from the 21-bp Tax response elements (TRE) from the HTLV-1 LTR to generate TRE-containing chimeric HIVs (TRE-HIVs). The TRE-HIVs exhibit selective replication and cell killing in HTLV-infected human CD4+ T cells, but not in HTLV-negative T cells. Transient transfections suggested that Tax-TRE interactions could account for the observed replication specificity. The TRE-containing HIV LTRs were synergistically activated by the HIV Tat and HTLV-1 Tax transactivators. These results demonstrate that it is possible to specifically target HIV replication and 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-1-infected cells based on alterations of the LTR transcriptional regulatory elements. They also suggest that HIV Tat can cooperate with heterologous transcriptional activators, such as Tax, which act through upstream binding sites without directly binding to DNA.
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes; D002460:Cell Line; D002470:Cell Survival; D002678:Chimera; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D015696:Gene Products, tat / Q000096:biosynthesis / Q000378:metabolism*; D016356:Gene Products, tax / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006678:HIV / Q000235:genetics / Q000502:physiology*; D016325:HIV Long Terminal Repeat; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping; D014162:Transfection; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016356:Gene Products, tax; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D015500:Chloramphenicol O-Acetyltransferase