Flavivirus NS5A proteins for the treatment of HIV
GB virus C (GBV-C or hepatitis G virus) is a flavivirus that frequently leads to chronic viremia in humans. The invention provides compositions and methods involving a -GBV-C NS5A peptide or polypeptide for inhibiting and treating HIV infections.
1. A pharmaceutical composition comprising an isolated peptide comprising at most 80 contiguous amino acids of NS5A, wherein the peptide comprises the amino acid sequence of VDGIPV(S/E)WDA(D/E)ARAPA) (SEQ ID NO: 24) or (V/L)DG(I/V)X(S/H)(W/R)XA(D/P)XXXPX (SEQ ID NO: 25), wherein X is any amino acid.
2. The composition of claim 1 , comprising two or more peptides and/or peptide mimetics.
3. The composition of claim 1 , wherein the peptide is a fusion peptide.
4. The composition of claim 3 , wherein the fusion peptide includes a targeting domain.
5. The composition of claim 4 , wherein the targeting domain targets the endoplasmic reticulum.
6. The composition of claim 4 , wherein the targeting domain targets a cell surface receptor.
7. The composition of claim 6 , wherein the cell surface receptor is the CD4 receptor.
8. The composition of claim 1 , wherein the peptide is formulated in a lipid vehicle.
9. The composition of claim 8 , wherein the lipid vehicle is a liposome.
10. The composition of claim 1 , wherein the peptide is formulated with an amphipathic peptide, an insect peptide, or pyrrhocoricin.
11. The composition of claim 1 , wherein the peptide comprises residues 152-167 of GBV-C NS5A, or the corresponding sequences from other flavivirus NS5A proteins.
12. A method for treating HIV infection comprising administering to a subject a composition comprising an isolated peptide comprising at most 80 contiguous amino acids of NS5A, wherein the peptide comprises an amino acid sequence VDGIPV(S/E)WDA(D/E)ARAPA (SEQ ID NO: 24) or (V/L)DG(I/V)X(S/H)(W/R)XA(D/P)XXXPX (SEQ ID NO: 25), wherein X is any amino acid.
13. The method of claim 12 , wherein the peptide is a GBV-C NS5A peptide.
14. The method of claim 12 , further comprising administration of at least a second anti-HIV therapy.
15. The method of claim 12 , wherein the composition is administered at least twice.
16. A method for treating HIV infection comprising administering to a subject a composition comprising an expression construct encoding a peptide comprising at most 80 contiguous amino acids of NS5A, wherein said peptide comprises an amino acid sequence of VDGIPV(S/E)WDA(D/E)ARAPA (SEQ ID NO: 24) or (V/L)DG(I/V)X(S/H)(W/R)XA(D/P)XXXPX (SEQ ID NO: 25), wherein X is any amino acid.
17. The method of claim 16 , wherein the peptide further comprises a targeting domain.
18. The method of claim 17 , wherein the targeting domain targets a cell surface receptor.
19. A method for modulating CD4 expression in a T cell of a subject comprising providing to a subject a peptide comprising at most 80 contiguous amino acids of NS5A, wherein said peptide comprises an amino acid sequence of VDGIPV(S/E)WDA(D/E)ARAPA (SEQ ID NO: 24) or (V/L)DG(I/V)X(S/H)(W/R)XA(D/P)XXXPX (SEQ ID NO: 25), wherein X is any amino acid.
20. The method of claim 19 , wherein the peptide is provided by administering an expression construct encoding the peptide.
21. The method of claim 19 , wherein the NS5A peptide further comprises a targeting domain.
22. The method of claim 21 , wherein the targeting domain is a nuclear targeting signal.
23. Then method of claim 21 , wherein the targeting domain targets the endoplasmic reticulum.
24. The method of claim 21 , wherein the targeting domain targets a cell surface receptor.
25. The method of claim 24 , wherein the cell surface receptor is the CD4 receptor.
26. A method for modulating T cell function, modulating chemokine product by a T cell, or inhibiting apoptosis in a T cell, comprising contacting a T cell with a flavivirus NS5A peptide comprising at most 80 contiguous amino acids of NS5A, wherein said peptide comprises an amino acid sequence of VDGIPV(S/E)WDA(D/E)ARAPA (SEQ ID NO: 24) or (V/L)DG(I/V)X(S/H)(W/R)XA(D/P)XXXPX (SEQ ID NO: 25), wherein X is any amino acid.
27. The method of claim 26 , wherein the peptide is encoded by an expression construct.
28. The method of claim 26 , wherein the peptide further comprises a targeting domain.
29. The method of claim 26 , wherein said T cell is in a subject.
30. The method of claim 29 , wherein said subject suffers from or is at risk of an allergic reaction, suffers from or is at risk of an autoimmune disease, or is or will be a transplant recipient.
31. The method of claim 28 , wherein the targeting domain is a nuclear targeting signal.
32. Then method of claim 28 , wherein the targeting domain targets the endoplasmic reticulum.
33. The method of claim 28 , wherein the targeting domain targets a cell surface receptor.
34. The method of claim 33 , wherein the cell surface receptor is the CD4 receptor.
35. The method of claim 17 , wherein the targeting domain is a nuclear targeting signal.
36. Then method of claim 17 , wherein the targeting domain targets the endoplasmic reticulum.
37. The method of claim 18 , wherein the cell surface receptor is the CD4 receptor.
38. The method of claim 12 , wherein the fusion peptide includes a targeting domain.
39. The method of claim 38 , wherein the targeting domain targets the endoplasmic reticulum.
40. The method of claim 38 , wherein the targeting domain targets a cell surface receptor.
41. The method of claim 40 , wherein the cell surface receptor is the CD4 receptor.