Induction of antibody responses that neutralize human T-cell leukemia virus type I infection in vitro and in vivo by peptide immunization

Abstract

In order to define neutralization regions on the envelope antigen of human T-cell leukemia virus type I (HTLV-I), we have generated a number of new anti-envelope gp46 monoclonal antibodies from rats and mice. Epitopes recognized by new monoclonal antibodies which could neutralize HTLV-I in syncytium and transformation inhibition assays were localized to sequences in gp46 from amino acids 186 to 193, 190 to 195, 191 to 195, 191 to 196, and 194 to 199. Ovalbumin-conjugated synthetic gp46 peptides containing these neutralization epitopes, pepl90-199 (a synthetic gp46 peptide containing amino acids 190 to 199) and pepl80-204, but not pepl85-194 or pepl94-203, could give rise to HTLV-I-neutralizing antibody responses in rabbits. These immune or nonimmune rabbits were then challenged with HTLV-I by intravenous inoculation with 5 x 107 live HTLV-I-producing ILT-8M2 cells. By a PCR assay, it was revealed that HTLV-I provirus was detected in peripheral blood lymphocytes from nonimmune and pep288-312-immunized rabbits, whereas the provirus was not detected in peripheral blood lymphocytes from pepl90-199and pepl80-204-immunized rabbits over an extended period. These results suggest that the induction of anti-gp46 neutralizing antibody responses by immunization with synthetic peptides has the potential to protect animals against HTLV-I infection in vivo.

Identification of exposed epitopes on the envelope glycoproteins of human T-cell lymphotropic virus type I (HTLV-I)

“…Thus, as proposed by Carrington et al (1996), the SUgp46 central region (aa175-200) could be folded so that only short stretches are exposed on the surface of the HTLV-I-envelope glycoproteins. aa190-199 appears to be the major exposed portion of the central region of the SU glycoprotein, which is consistent with the localization of neutralizing determinants in this domain (Baba et al, 1993;Tanaka et al, 1994). The domain aa287-311 also appears to be well exposed at the oligomer surface, as demonstrated by the high reactivity of all antibodies induced by the corresponding HB synthetic peptide.…”

“…Other antigenic determinants are localized in the amino-terminal region (aa53-75, aa89-110) (Horal et al, 1991;Desgranges et al, 1994) and in the carboxy-terminal region (aa239-261, aa287-311) of the SUgp46 (Horal et al, 1991;Desgranges et al, 1994). All these domains overlap potential linear neutralizing epitopes (Palker et al, 1992;Kuroki et al, 1992;Baba et al, 1993;Tanaka et al, 1994;Desgranges et al, 1994).…”

“…When synthetic peptides were used as immunogens, it appeared that the larger the peptide (aa180-204), the better neutralizing response it generated. For instance, Tanaka et al (1994) have observed that the synthetic peptide aa180-204 was more efficient in inducing a long-term protective response in rabbits than the aa190-199 peptide. A larger synthetic peptide may more efficiently mimic the native structure of the antigen and favor the production of neutralizing antibodies.…”

“…The central region of SUgp46 (aa175-212) is the immunodominant domain of the HTLV-I envelope proteins (Horal et al, 1991). This region harbors several linear epitopes that induce neutralizing antibodies (Kuroki et al, 1992;Baba et al, 1993;Tanaka et al, 1994;Desgranges et al, 1994). However, neutralizing epitopes have also been identified outside this immunodominant region, e.g., in the amino-terminal part of SUgp46 sub-unit that maps between aa90-98 (Palker et al, 1992).…”

“…Theorically, synthetic peptide immunogens have the advantage of eliciting selective immune responses against viral infection without triggering harmful responses to host tissues, in contrast to conventional vaccines that use attenuated or killed strains of the pathogenic organism and recombinant protein products (Lairmore et al, 1995). Several studies have used synthetic peptides that constitute the relevant neutralization epitopes of HTLV-I envelope proteins to protect rabbits against viral infection and have shown that synthetic peptides overlapping the central region of SUgp46 could be protective, but not in all cases (Tanaka et al, 1994).…”