The United States of America, As Represented by the Secretary, Department of Health and Human Services

The United States of America As Represented by the Department of Health

Jeffrey D Ahlers

Jay A Berzofsky

Peter L Nara

Mutsunori Shirai

C David Pendleton

C David Pendelton

Peptide constructs comprised of multideterminant T helper peptides from the envelope glycoprotein of HIV previously identified to induce proliferative responses in four different haplotypes of mice and IL-2 responses in 52-73% of HIV positive, flu positive patients (cluster peptides), were co-linearly synthesized with the peptide 18 of the V3 loop of HIV-1 gp 160, corresponding to the principal neutralizing determinant of HIV-IIIB and also shown to contain a dominant CTL epitope. Cognate help for peptide 18 antibody was elicited following a single immunization in all strains of mice which had previously responded to a T cell epitope encompassed by the peptides. In two strains of mice, the level of neutralizing antibody achieved was comparable to levels adequate for protection from homologous viral challenge in chimpanzees. After a single boost, much higher antibody titers for 90% neutralization in the range of 1:1000 to 1:16,000 were achieved. Spleen cells from mice of three distinct MHC haplotypes sharing the Dclass I MHC molecule but with different class II molecules, immunized with the compound peptides, exhibited enhanced gp160-specific CTL activity.

Peptides which elicit a high neutralizing antibody titer, cytotoxic T lymphocyte response and T helper cell response in a broad range of MHC type recipients

Peptide constructs comprised of multideterminant T helper peptides from the envelope glycoprotein of HIV previously identified to induce proliferative responses in four different haplotypes of mice and IL-2 responses in 52-73% of HIV positive, flu positive patients (cluster peptides), were co-linearly synthesized with the peptide 18 of the V3 loop of HIV-1 gp 160, corresponding to the principal neutralizing determinant of HIV-IIIB and also shown to contain a dominant CTL epitope. Cognate help for peptide 18 antibody was elicited following a single immunization in all strains of mice which had previously responded to a T cell epitope encompassed by the peptides. In two strains of mice, the level of neutralizing antibody achieved was comparable to levels adequate for protection from homologous viral challenge in chimpanzees. After a single boost, much higher antibody titers for 90% neutralization in the range of 1:1000 to 1:16,000 were achieved. Spleen cells from mice of three distinct MHC haplotypes sharing the D,class I MHC molecule but with different class II molecules, immunized with the compound peptides, exhibited enhanced gp160-specific CTL activity.

Multideterminant peptides that elicit helper T-lymphocyte cytotoxic T-lymphocyte and neutralizing antibody responses against HIV-1

The invention is directed to peptides of the HIV-1 envelope protein presenting multiple immune determinants. The peptide elicits both humoral and cell-mediated immune responses in mice having a variety of MHC types. In other embodiments, the invention is directed to immunogens composed of the peptides and methods for immunization employing them.

Multideterminant peptides that elicit helper T-lymphocyte, cytotoxic T lymphocyte and neutralizing antibody responses against HIV-1

This invention is directed toward a multideterminant human immunodeficiency virus type 1 (HIV-1) peptide which comprises a covalently linked T-helper (Th) lymphocyte epitope, cytotoxic T-lymphocyte (CTL) epitope, and an epitope capable of eliciting a neutralizing antibody response (AbN), wherein said peptide has the following amino acid sequence: KQIINMWQEVGKAMYAPPISGQIRRIHIGPGRAFYTTKN. This peptide has the further characteristic of evoking all three of these immune responses in hosts having a broad range of major histocompatibility complex (MHC) types. This peptide is useful as an immunogen to generate broad immune responses in a host, to assess immune responses in virally infected hosts, and as a diagnostic reagent to detect viral infection.

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Kensington, MD, United States of America

Jeffrey D Ahlers