Recombinant gp120 protein with V1-loop deletion
Inventors
Franchini, Genoveffa • Cardozo, Timothy • Becerra-Flores, Manuel • Silva de Castro, Isabela • Gorini, Giacomo • Bissa, Massimiliano
Assignees
New York University NYU • US Department of Health and Human Services
Publication Number
US-12162910-B2
Publication Date
2024-12-10
Expiration Date
2039-10-21
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Abstract
Embodiments of recombinant HIV-1 gp120 proteins that contain a V1 deletion are disclosed. Also provided are gp140, gp145, and gp160 proteins containing the V1 deletion, as well as HIV-1 Env ectodomain trimers containing protomers containing the V1 deletion. Nucleic acid molecules encoding these proteins are also provided. In several embodiments, the disclosed recombinant HIV-1 proteins and/or nucleic acid molecules can be used to generate an immune response to HIV-1 in a subject, for example, to treat or prevent an HIV-1 infection in the subject.
Core Innovation
The invention provides recombinant HIV-1 gp120 proteins that contain a specific deletion in the V1 loop comprising HIV-1 Env residues 137-152 as defined by the HXBc2 numbering system. This modification unmasks epitopes in the V2 region that are otherwise conformationally masked by the V1 domain and have been difficult to target with effective immunogens. The recombinant gp120 proteins, as well as gp140, gp145, gp160 proteins, and HIV-1 Env ectodomain trimers containing the V1 deletion, are included among the embodiments.
The problem addressed by this invention stems from the antigenic variation and glycosylation of the HIV-1 Env protein, which conceals conserved epitopes and makes it difficult to elicit effective neutralizing responses against HIV-1. Prior immunogens with intact V1V2 regions have failed to elicit protective V2-oriented antibody responses. The disclosed proteins with the V1 domain deletion expose and enhance the immunogenicity of V2 epitopes, leading to a more effective protective immune response, as demonstrated in an animal model.
The invention encompasses not only the proteins themselves but also nucleic acid molecules encoding these proteins, immunogenic compositions containing them (optionally with adjuvant), and diagnostic or prognostic methods based on immune response to specific V2 epitopes. The recombinant gp120 and Env proteins with the V1 deletion can be administered alone or as part of a prime-boost immunization regimen to elicit an immune response that inhibits or prevents HIV-1 infection in a subject.
Claims Coverage
The patent contains multiple independent claims covering the core inventive features of recombinant HIV-1 Env proteins with a V1-loop deletion, related proteins, trimers, nucleic acids, compositions, virus-like particles, immunization methods, and diagnostic applications.
Recombinant gp120 protein with V1-loop deletion
A recombinant gp120 protein comprising a deletion consisting of HIV-1 Env residues 137-152 (according to the HXBc2 numbering system), wherein the recombinant gp120 protein comprises or consists of an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 1-3, and the recombinant gp120 protein elicits an immune response to HIV-1.
Recombinant gp140, gp145, or gp160 proteins containing V1-loop deleted gp120
A recombinant gp140, gp145, or gp160 protein comprising the recombinant gp120 protein with the V1-loop deletion as described, such that the protein elicits an immune response to HIV-1.
Recombinant HIV-1 Env ectodomain trimer containing V1-loop deleted gp120
A recombinant HIV-1 Env ectodomain trimer comprising protomers that each include the V1-loop deleted recombinant gp120 protein and a gp41 ectodomain, wherein the trimer elicits an immune response to HIV-1.
Defined amino acid sequence and structure of recombinant proteins and trimers
The recombinant proteins and trimers are further defined by comprising or consisting of specific HIV-1 Env residue ranges (for gp120: 31-507; for gp41 ectodomain: 512-664), and include versions wherein protomers comprise or consist of an amino acid sequence at least 90% identical to SEQ ID NOs: 4-5 and 66.
Trimer structure variants and fusions
The recombinant HIV-1 Env ectodomain trimer may be soluble, membrane-anchored (fused C-terminally to a transmembrane domain), or contain a C-terminal fusion to a trimerization domain via a peptide linker or directly.
Immunogenic conjugates and virus-like particles
Conjugates comprising the recombinant gp120 protein with a heterologous carrier, and virus-like particles including the recombinant gp120, gp140, gp145, gp160, or recombinant HIV-1 Env ectodomain trimer containing V1-loop deleted gp120.
Immunogenic compositions and methods
An immunogenic composition comprising the recombinant proteins or trimers, with or without adjuvant, for use in eliciting an immune response to HIV-1 in a subject, and methods of administering an effective amount of such proteins to elicit the immune response or to treat/inhibit HIV-1 infection in a subject.
The inventive features of this patent comprehensively cover recombinant HIV-1 envelope proteins with V1-loop deletions, their configurations as monomers, trimers, virus-like particles, as well as pharmaceutical compositions, immunogenic conjugates, and broad methods for immunization and treatment against HIV-1. Key technical distinctions are the defined V1-loop deletion, specified sequence identities, and applications in vaccination and immune response elicitation.
Stated Advantages
Exposure of V2 epitopes by V1-loop deletion allows the recombinant gp120 or Env proteins to elicit a surprisingly effective immune response that inhibits HIV-1 infection.
The V1-deleted immunogen yields a protective immune response in animal models, unlike prior V1-deleted HIV-1 immunogens which failed to elicit V2-directed antibody responses.
The deletion of V1 residues increases accessibility to V2 and enhances binding to relevant antibodies and soluble CD4, indicating improved immunogenicity.
Documented Applications
Eliciting an immune response to HIV-1 envelope protein in a subject to treat, inhibit, or prevent HIV-1 infection.
Immunogenic compositions and vaccination in subjects, including at-risk or infected humans, to induce a protective immune response against HIV-1.
Use in diagnostic or prognostic methods to determine the likelihood or type of immune response to HIV-1 in a subject based on antibody binding to specific V2 peptides.
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