HIV-1 GP140 immunogens comprising modified NHR1 regions that stabilize pre-fusion envelope conformations

Patent metadata

Field	Value
Publication number	US-11767347-B2
Application number	US-202117553070-A
Country	US
Kind code	B2
Filing date	Dec 16, 2021
Priority date	May 2, 2016
Publication date	Sep 26, 2023
Grant date	Sep 26, 2023

Abstract

The present invention provides HIV-1 vaccine immunogens. Some of the immunogens contain a soluble gp140-derived protein that harbors a modified N-terminus of the HR1 region in gp41. Some of the immunogens contain an HIV-1 Env-derived trimer protein that is presented on a nanoparticle platform. The invention also provides methods of using the HIV-1 vaccine immunogens for eliciting an immune response or treating HIV infections.

First claim

What is claimed is:

1. A HIV-1 vaccine composition, comprising an HIV-1 Env-derived trimer immunogen presented on a self-assembling nanoparticle or a virus-like particle (VLP), wherein the HIV-1 Env-derived trimer immunogen is a modified gp140 protein comprising a gp120 polypeptide and a gp41 polypeptide, wherein amino acid residues 548-568 of the N-terminus of heptad 1 region (HR1) of the gp41 polypeptide is replaced with a loop sequence of 6 to 14 amino acid residues in length that stabilizes the pre-fusion gp140 structure, wherein the numbering of the amino acid residues corresponds to HxB2 nomenclature.

2. The HIV-1 vaccine composition of claim 1 , wherein the self-assembling nanoparticle comprises dihydrolipoyl acyltransferase (E2P), ferritin, or lumazine synthase (LS).

3. The HIV-1 vaccine composition of claim 1 , wherein the gp41 polypeptide is gp41 ECTO .

4. The HIV-1 vaccine composition of claim 1 , wherein the gp120 and gp41 polypeptides are from different HIV-1 strains.

5. The HIV-1 vaccine composition of claim 1 , wherein the modified HIV-1 gp140 protein is derived from HIV-1 strain BG505.

6. The HIV-1 vaccine composition of claim 1 , wherein the loop sequence comprises (GS)n (SEQ ID NO:23), wherein n is any integer between 3 and 7, inclusive.

7. The HIV-1 vaccine composition of claim 1 , wherein the loop sequence comprises (GS) 4 (SEQ ID NO:24).

8. The HIV-1 vaccine composition of claim 1 , wherein the loop sequence comprises 10 amino acid residues.

9. The HIV-1 vaccine composition of claim 8 , wherein the loop sequence comprises any one of SEQ ID NOs:1-5.

10. The HIV-1 vaccine composition of claim 1 , wherein the loop sequence comprises 8 amino acid residues.

11. The HIV-1 vaccine composition of claim 10 , wherein the loop sequence comprises any one of SEQ ID NOs:6-10.

12. The HIV-1 vaccine composition of claim 1 , wherein the modified HIV-1 envelope gp140 protein further comprises a flexible linker sequence that substitutes for the cleavage site sequence between gp120 and gp41.

13. The HIV-1 vaccine composition of claim 12 , wherein the linker sequence comprises (G 4 S) 2 (SEQ ID NO:22) or SGS and substitutes for residues 508-511 at the cleavage site.

14. The HIV-1 vaccine composition of claim 12 , wherein the linker sequence comprises 8 amino acid residues and substitutes for residues 501-518 at the cleavage site, and wherein numbering of the amino acid residues corresponds to that of HIV-1 strain BG505. SOSIP.664 gp140.

15. The HIV-1 vaccine composition of claim 14 , wherein the linker sequence comprises the sequence shown in any one of SEQ ID NOs:16-20.

16. The HIV-1 vaccine composition of claim 1 , wherein the modified HIV-1 envelope gp140 protein further comprises an engineered disulfide bond between gp120 and gp41.

17. The HIV-1 vaccine composition of claim 16 , wherein the engineered disulfide bond is between residues A501C and T605C.

18. The HIV-1 vaccine composition of claim 1 , wherein the gp41 ECTO polypeptide is derived from HIV-1 strain BG505, and wherein the N-terminus of heptad 1 region (HR1) (SEQ ID NO:28) in the gp41 ECTO polypeptide is replaced with a loop sequence shown in SEQ ID NO:6.

19. The HIV-1 vaccine composition of claim 1 , wherein the modified HIV-1 envelope gp140 protein further comprises (a) a linker sequence (G 4 S) 2 (SEQ ID NO:22) that substitutes for residues 508-511 at the cleavage site, and (b) an engineered disulfide bond between residues A501C and T605C.

20. A polynucleotide encoding the subunit sequence of the HIV-1 vaccine composition of claim 1 .

21. A method of treating or preventing HIV-1 infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the HIV-1 vaccine composition of claim 1 , thereby treating or preventing HIV-1 infection in the subject.

Assignees

• Scripps Research Inst

Inventors

• Kong Leopold
• Wilson Ian A
• De Val Natalia
• Ward Andrew B
• Burton Dennis
• He Linling
• Zhu Jiang

Classifications

• C07K14/162 Primary

  env, e.g. gp160, gp110/120, gp41, V3, peptid T, CD4-Binding site · CPC title

• A61K39/21

  Retroviridae, e.g. equine infectious anemia virus · CPC title

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• C07K14/005 Primary

  from viruses · CPC title

• A61K39/12

  Viral antigens · CPC title