SEQUENCE-ANALYSIS OF AN IMMUNOGENIC AND NEUTRALIZING DOMAIN OF THE HUMAN T-CELL LYMPHOMA LEUKEMIA-VIRUS TYPE-I GP46 SURFACE-MEMBRANE PROTEIN AMONG VARIOUS PRIMATE T-CELL LYMPHOMA LEUKEMIA-VIRUS ISOLATES INCLUDING THOSE FROM A PATIENT WITH BOTH HTLV-I-ASSOCIATED MYELOPATHY AND ADULT T-CELL LEUKEMIA

Human T-cell lymphoma/leukemia virus type I (HTLV-I) causes adult T-ce ll leukemia/lymphoma and HTLV-I-associated myelopathy. Specific region s within the outer envelope proteins of other retroviruses, e.g., huma n immunodeficiency virus type 1, are highly immunogenic and, because o f the selective pressure of the host immune system, quite variable. Mu tations in the external envelope protein gene of murine retroviruses a nd human immunodeficiency virus type 1 influence cellular tropism and disease pathogenesis. By contrast, no disease-specific viral mutations have been identified in HTLV-I-infected patients. However, all isolat es studied thus far have originated from leukemic cell lines, peripher al blood mononuclear cells, or cerebrospinal fluid lymphocytes from pa tients with HTLV-I-associated myelopathy and adult T-cell leukemia/lym phoma and, therefore, may not truly reflect tissue-associated variatio n. The midregion of the HTLV-I gp46 external envelope glycoprotein (am ino acids 190-209) induces an antibody response in 90% of infected ind ividuals, and a hexapeptide in this region (amino acids 191-196) elici ts antibodies in rabbits which inhibit syncytia formation and infectio n of target lymphocytes. Because of the above, we expected the neutral izing domain of the gp46 env gene of HTLV-I to possess disease or orga n-associated mutations selected by the infected host's immune system. Hence, we amplified, cloned, and sequenced HTLV-I DNA directly from in vivo central nervous system, spleen, and kidney specimens, and a leuk emic cell line from a patient (M. J.) with both HTLV-I-associated myel opathy and adult T-cell leukemia/lymphoma to discern the possibility o f tissue- and/or disease-specific variants. In addition, we sequenced several HTLV-I isolates from different regions of the world, including Papua New Guinea, Bellona, and Liberia, and compared them to other pr eviously published HTLV-I and related retroviral sequences. The 239-ba se pair sequence corresponding to amino acids 178 to 256 in gp46 displ ayed minor tissue-specific variation in clones derived from central ne rvous system tissues from patient M. J., but overall was highly conser ved at both the DNA and amino acid levels. Variation was observed in t his region among the other HTLV-I, simian T-cell lymphoma virus type I and HTLV-II isolates in a pattern that was consistent with their know n phylogenetic relationship. No consistent disease-related changes wer e observed. Although the neutralizing domains of HTLV-I and simian T-c ell lymphoma virus type I differ considerably from that of HTLV-II, al most absolute conservation of these six amino acid residues was observ ed among the substrains of these two major strains of the primate T-ce ll lymphoma/leukemia viruses.