A novel human retrovirus, termed HTLV-4, has recently been isolated from West African individuals at high risk for sexually transmissible diseases. This newly discovered virus is related to HIV in its tropism for OKT4 lymphocytes, the antigenicity of its core proteins, and its in vitro growth characteristics but is clearly distinct from the AIDS virus in its ultrastructure, the size and antigenicity of its envelope proteins, its genomic nucleotide sequence, and its apparent clinical sequelae. The existence of these two viruses --both tropic for OKT4-positive cells yet possessing major differences in nucleotide sequence, protein structure, and biologic activity -- provides a unique opportunity to study the molecular biology and structure-function relationships of both HIV and HTLV-4. We propose to employ nucleotide sequence analysis, recombinant DNA technology, and in vitro biologic characterization to define the genetic organization of HTLV-4 and to elucidate the genes and gene products of HTLV-4 and HIV that are responsible for certain of their critical biologic functions. Specific research aims are as follows: 1) To analyze by molecular cloning and nucleotide sequence determination the genomic organization of HTLV-4; 2) To determine at a nucleotide sequence level the extent and nature of genetic relatedness of HTLV-4 to the AIDS virus (HIV) and to other related primate and ungulate retroviruses; 3) To utilize the above-mentioned molecular clones and sequence information to develop transfection-derived, genetically-pure viral strains of HTLV-4; 4) To compare and contrast the in vitro biologic properties of HTLV- 4 and HIV using genetically-defined (transfection-derived) strains of both viruses; 5) To analyze the envelope of HTLV-4 and HIV by comparative sequence analysis and by experiments utilizing genetic recombination, site-directed mutagenesis, competitive peptide inhibition, and monoclonal antibodies so as to identify and characterize biologically-important envelope domains of both viruses that are responsible for viral envelope-T4 (CD4) binding; 6) To develop recombinant-derived and expressed envelope and core proteins of HTLV-4 for serological testing and differentiation of HTLV-4 from HIV.
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