CA2360347A1 - Improved expression of hiv polypeptides and production of virus-like particles - Google Patents

Improved expression of hiv polypeptides and production of virus-like particles Download PDF

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CA2360347A1
CA2360347A1 CA002360347A CA2360347A CA2360347A1 CA 2360347 A1 CA2360347 A1 CA 2360347A1 CA 002360347 A CA002360347 A CA 002360347A CA 2360347 A CA2360347 A CA 2360347A CA 2360347 A1 CA2360347 A1 CA 2360347A1
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seq
polypeptide
cell
expression cassette
vector
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CA2360347C (en
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Susan Barnett
Jan Zur Megede
Indresh Srivastava
Ying Lian
Karin Hartog
Hong Liu
Catherine Greer
Mark Selby
Christopher Walker
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Novartis Vaccines and Diagnostics Inc
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Abstract

The present invention relates to the efficient expression of HIV polypeptide s in a variety of cell types, including, but not limited to, mammalian, insect, and plant cells. Synthetic expression cassettes encoding the HIV Gag-containing polypeptides arc described, as are uses of the expression cassettes in applications including DNA immunization, generation of packaging cell lines, and production of Env-, tat- or Gag-containing proteins. The inventio n provides methods of producing Vitus-Like Particles (VLPs), as well as, uses of the VLPs including, but not limited to, vehicles for tire presentation of antigens and stimulation of immune response in subjects to whom the VLPs are administered.

Claims (90)

1. An expression cassette, comprising a polynucleotide sequence encoding a polypeptide including an HIV Gag polypeptide, wherein the polynucleotide sequence encoding said Gag polypeptide comprises a sequence having at least 90% sequence identity to the sequence presented as SEQ ID NO:20.
2. The expression cassette of claim 1, comprising, a polynucleotide sequence encoding a polypeptide including an HIV Gag polypeptide, wherein the polynucleotide sequence encoding said Gag polypeptide comprises a sequence having at least 90% sequence identity to the sequence presented as SEQ ID NO:9.
3. The expression cassette of claim 1, wherein said polynucleotide sequence encoding a polypeptide including an HIV Gag polypeptide comprises a sequence having at least 90% sequence identity to the sequence presented as SEQ ID NO:4.
4. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HIV protease polypeptide.
5. The expression cassette of claim 4,wherein the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90% sequence identity to a sequence selected from the group consisting of: SEQ ID
NO:5, SEQ ID NO:78, and SEQ ID NO:79.
6. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HIV reverse transcriptase polypeptide.
7. The expression cassette of claim 6, wherein the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90% sequence identity to a sequence selected from the group consisting of: SEQ ID
NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, and SEQ
ID NO:84.
8. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HIV tat polypeptide.
9. The expression cassette of claim 8, wherein the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90% sequence identity to a sequence selected from the group consisting of: SEQ ID
NO:86, SEQ ID NO:87, SEQ ID NO:88 and SEQ ID NO:89.
10. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HIV polymerase polypeptide, wherein the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90%
sequence identity to the sequence presented as SEQ ID
NO:6.
11. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HIV polymerase polypeptide, wherein (i) the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90%

sequence identity to the sequence presented as SEQ ID
NO:4, and (ii) wherein the sequence is modified by deletions of coding regions corresponding to reverse transcriptase and integrase.
12. The expression cassette of claim 11, wherein said polynucleotide sequence preserves T-helper cell and CTL epitopes.
13. The expression cassette of claim 1, wherein said polynucleotide sequence further includes a polynucleotide sequence encoding an HCV core polypeptide, wherein the nucleotide sequence encoding said polypeptide comprises a sequence having at least 90% sequence identity to the sequence presented as SEQ ID NO:7.
14. An expression cassette, comprising a polynucleotide sequence encoding a polypeptide including an HIV Env polypeptide, wherein the polynucleotide sequence encoding said Env polypeptide comprises a sequence having at least 90% sequence identity to SEQ ID
NO:71 (Figure 58) or SEQ ID NO:72 (Figure 59).
15. The expression cassette of claim 14, wherein said Env polypeptide includes sequences flanking a V1 region but has a deletion in the V1 region itself.
16. The expression cassette of claim 15, wherein the polynucleotide sequence encoding the polypeptide comprises the sequence presented as SEQ ID NO:65 (Figure 52 gp160.modUS4.de1V1).
17. The expression cassette of claim 14, wherein said Env polypeptide includes sequences flanking a V2 region but has a deletion in the V2 region itself.
18. The expression cassette of claim 17, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:60 (Figure 47); and SEQ ID NO:66 (Figure 53).
19. The expression cassette of claim 17, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:34 (Figure 20); SEQ ID NO:37 (Figure 24); SEQ ID NO:40 (Figure 27); SEQ ID NO:43 (Figure 30); SEQ ID NO:46 (Figure 33); SEQ ID NO:49 (Figure 36); and SEQ ID NO:76 (Figure 64).
20. The expression cassette of claim 14, wherein said Env polypeptide includes sequences flanking a V1/V2 region but has a deletion in the V1/V2 region itself.
21. The expression cassette of claim 20, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:59 (Figure 46); SEQ ID NO:61 (Figure 48); SEQ ID NO:67 (Figure 54); and SEQ ID NO:75 (Figure 63).
22. The expression cassette of claim 20, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:35 (Figure 21); SEQ ID NO:38 (Figure 25); SEQ ID NO:41 (Figure 28); SEQ ID NO:44 (Figure 31); SEQ ID NO:47 (Figure 34) and SEQ ID NO:50 (Figure 37).
23. The expression cassette of claim 14, wherein said Env polypeptide has a mutated cleavage site that prevents the cleavage of a gp140 polypeptide into a gp120 polypeptide and a gp41 polypeptide.
24. The expression cassette of claim 23, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:57 (Figure 44); SEQ ID NO:61 (Figure 48); and SEQ ID NO:63 (Figure 50).
25. The expression cassette of claim 23, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:39 (Figure 26); SEQ ID NO:40 (Figure 27); SEQ ID NO:41 (Figure 28); SEQ ID NO:42 (Figure 29); SEQ ID NO:43 (Figure 30); SEQ ID NO:44 (Figure 31); SEQ ID NO:45 (Figure 32); SEQ ID NO:46 (Figure 33); and SEQ ID NO:47 (Figure 34).
26. The expression cassette of claim 14, wherein said Env polypeptide includes a gp160 Env polypeptide or a polypeptide derived from a gp160 Env polypeptide.
27. The expression cassette of claim 26, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:64 (Figure 51); SEQ ID NO:65 (Figure 52); SEQ ID NO:66 (Figure 53); SEQ ID NO:67 (Figure 54); SEQ ID NO:68 (Figure 55); SEQ ID NO:75 (Figure 63); and SEQ ID NO:73 (Figure 61).
28. The expression cassette of claim 26, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:48 (Figure 35); SEQ ID NO:49 (Figure 36); SEQ ID NO:50 (Figure 37); SEQ ID NO:76 (Figure 64); and SEQ ID NO:74 (Figure 62).
29. The expression cassette of claim 14, wherein said Env polypeptide includes a gp140 Env polypeptide or a polypeptide derived from a gp140 Env polypeptide.
30. The expression cassette of claim 29, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:56 (Figure 43); SEQ ID NO:57 (Figure 44); SEQ ID NO:58 (Figure 45); SEQ ID NO:59 (Figure 46); SEQ ID NO:60 {Figure 47); SEQ ID NO:61 (Figure 48); SEQ ID NO:62 (Figure 49); and SEQ ID NO:63 (Figure 50).
31. The expression cassette of claim 29, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:36 (Figure 23); SEQ ID NO:37 (Figure 24); SEQ ID NO:38 (Figure 25); SEQ ID NO:39 (Figure 26); SEQ ID NO:40 (Figure 27); SEQ ID NO:41 (Figure 28); SEQ ID NO:42 (Figure 29); SEQ ID NO:43 (Figure 30); SEQ ID NO:44 (Figure 31); SEQ ID NO:45 (Figure 32); SEQ ID NO:46 (Figure 33); and SEQ ID NO:47 (Figure 34).
32. The expression cassette of claim 14, wherein said Env polypeptide includes a gp120 Env polypeptide or a polypeptide derived from a gp120 Env polypeptide.
33. The expression cassette of claim 32, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:54 (Figure 41); and SEQ ID NO:55 (Figure 42).
34. The expression cassette of claim 32, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:33 (Figure 19); SEQ ID NO:34 {Figure 20); and SEQ ID NO:35 (Figure 21).
35. The expression cassette of claim 14, wherein the polynucleotide sequence encoding the polypeptide is selected from the group consisting of: SEQ ID NO:55 (Figure 42); SEQ ID NO:62 (Figure 49); SEQ ID NO:63 (Figure 50); and SEQ ID NO:68 (Figure 55).
36. A recombinant expression system for use in a selected host cell, comprising, an expression cassette of any of claims 1-35, and wherein said polynucleotide sequence is operably linked to control elements compatible with expression in the selected host cell.
37. The recombinant expression system of claim 36, wherein said control elements are selected from the group consisting of a transcription promoter, a transcription enhancer element, a transcription termination signal, polyadenylation sequences, sequences for optimization of initiation of translation, and translation termination sequences.
38. The recombinant expression system of claim 36, wherein said transcription promoter is selected from the group consisting of CMV, CMV+intron A, SV40, RSV, HIV-Ltr, MMLV-ltr, and metallothionein.
39. A cell comprising an expression cassette of any of claims 1-35, and wherein said polynucleotide sequence is operably linked to control elements compatible with expression in the selected cell.
40. The cell of claim 39, wherein the cell is a mammalian cell.
41. The cell of claim 40, wherein the cell is selected from the group consisting of BHK, VERO, HT1080, 293, RD, COS-7, and CHO cells.
42. The cell of claim 41, wherein said cell is a CHO cell.
43. The cell of claim 39, wherein the cell is an insect cell.
44. The cell of claim 43, wherein the cell is either Trichoplusia ni (Tn5) or Sf9 insect cells.
45. The cell of claim 39, wherein the cell is a bacterial cell.
46. The cell of claim 39, wherein the cell is a yeast cell.
47. The cell of claim 39, wherein the cell is a plant cell.
48. The cell of claim 39, wherein the cell is an antigen presenting cell.
49. The cell of claim 4B, wherein the lymphoid cell is selected from the group consisting of macrophage, monocytes, dendritic cells, B-cells, T-cells, stem cells, and progenitor cells thereof.
50. The cell of claim 39, wherein the cell is a primary cell.
51. The cell of claim 39, wherein the cell is an immortalized cell.
52. The cell of claim 39, wherein the cell is a tumor-derived cell.
53. A method for producing a polypeptide including HIV Gag polypeptide sequences, said method comprising, incubating the cells of claim 39, under conditions for producing said polypeptide.
54. A method for producing virus-like particles (VLPs), comprising, incubating the cells of claim 39, under conditions for producing said VLPs.
55. A method for producing a composition of virus-like particles (VLPs), comprising, (a) incubating the cells of claim 39, under conditions for producing said VLPs; and (b) substantially purifying said VLPs to produce a composition of VLPs.
56. A cell line useful for packaging lentivirus vectors, comprising suitable host cells that have been transfected with an expression vector containing an expression cassette of any of claims 1-35, and wherein said polynucleotide sequence is operably linked to control elements compatible with expression in the host cell.
57. The cell line of claim 56, wherein suitable host cells have been transfected with an expression vector containing the expression cassette of any of claims 1-13.
58. The cell line of claim 56, wherein suitable host cells have been transfected with an expression vector containing the expression cassette of claim 1-3.
59. The cell line of claim 56, wherein suitable host cells have been transfected with an expression vector containing the expression cassette of claim 14-35.
60. A gene delivery vector for use in a Mammalian subject, comprising a suitable gene delivery vector for use in said subject, wherein the vector comprises an expression cassette of any of claims 1-35, and wherein said polynucleotide sequence is operably linked to control elements compatible with expression in the subject.
61. A method of DNA immunization of a subject, comprising, introducing a gene delivery vector of claim 60 into said subject under conditions that are compatible with expression of said expression cassette in said subject.
62. The method of claim 61, wherein said gene delivery vector is a nonviral vector.
63. The method of claim 61, wherein said vector is delivered using a particulate carrier.
64. The method of claim 63, wherein said vector is coated on a gold or tungsten particle and said coated particle is delivered to said subject using a gene gun.
65. The method of claim 63, wherein said vector is encapsulated in a liposome preparation.
66. The method of claim 61, wherein said vector is a viral vector.
67. The method of claim 66, wherein said viral vector is a retroviral vector.
68. The method of claim 67, wherein said viral vector is a lentiviral vector.
69. The method of claim 61, wherein said subject is a mammal.
70. The method of claim 69, wherein said mammal is a human.
71. A method of generating an immune response in a subject, comprising transfecting cells of said subject a gene delivery vector of claim 60, under conditions that permit the expression of said polynucleotide and production of said polypeptide, thereby eliciting an immunological response to said polypeptide.
72. The method of claim 71, wherein said vector is a nonviral vector.
73. The method of claim 72, wherein said vector is delivered using a particulate carrier.
74. The method of claim 73, wherein said vector is coated on a gold or tungsten particle and said coated particle is delivered to said vertebrate cell using a gene gun.
75. The method of claim 73, wherein said vector is encapsulated in a liposome preparation.
76. The method of claim 71, wherein said vector is a viral vector.
77. The method of claim 76, wherein said viral vector is a retroviral vector.
78. The method of claim 77, wherein said viral vector is a lentiviral vector.
79. The method of claim 71, wherein said subject is a mammal.
80. The method of claim 79, wherein said mammal is a human.
81. The method of claim 71, wherein said transfecting is done ex vivo and said transfected cells are reintroduced into said subject.
82. The method of claim 71, wherein said transfecting is done in vivo in said subject.
83. The method of claim 71, where said immune response is a humoral immune response.
84. The method of claim 71, where said immune response is a cellular immune response.
85. A gene delivery vector comprising an alphavirus vector construct, wherein said alphavirus construct comprises an expression cassette according to any one of claims 1 through 35.
86. The gene delivery vector of claim 85, wherein the alphavirus vector construct is a cDNA vector construct.
87. The gene delivery vector of claim 85, wherein the alphavirus comprises a recombinant alphavirus particle preparation.
88. The gene delivery vector of claim 85, wherein the vector comprises a eukaryotic layered vector initiation system.
89. A method of stimulating an immune response in a subject comprising administering the gene delivery vector of any one of claims 85 through 88 in an amount effective to stimulate an immune response in said subject.
90. The method of claim 89, wherein the gene delivery vector is administered intramuscularly, intramucosally, intranasally, subcutaneously, intradermally, transdermall, intravaginally, intrarectally, orally or intravenously.
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