Constructs for enhancing immune responses
Chimeric protein constructs including a herpesvirus glycoprotein D (gD) and a heterologous polypeptide that interact with herpes virus entry mediator (HVEM) and enhance and enhance an immune response against the heterologous polypeptide and methods for their use are provided.
1. A nucleic acid molecule which encodes a fusion protein, wherein the fusion protein comprises:
(1) a first polypeptide segment comprising at least amino acids 1-240 of a mature Herpes simplex virus (HSV) glycoprotein D, wherein the first polypeptide segment does not comprise a full length mature glycoprotein D;
(2) a second polypeptide segment comprising at least one antigen, wherein the at least one antigen is not an HSV glycoprotein D antigen, wherein the N terminus of the second polypeptide segment is linked to the C terminus of the first polypeptide segment; and
(3) a third polypeptide segment comprising a C terminal portion of the HSV glycoprotein D, wherein the N terminus of the third polypeptide segment is linked to the C terminus of the second polypeptide segment,
wherein the at least one antigen is selected from the group consisting of:
an influenza virus antigen;
a nucleoprotein P influenza virus antigen;
a Plasmodium antigen;
a Plasmodium antigen selected from the group consisting of thrombospondin-related anonymous protein (TRAP), ring-infected erythrocyte surface antigen (RESA), merozoite surface protein 1 (MSP1), merozoite surface protein 2 (MSP2), merozoite surface protein 3 (MSP3), and glutamate-rich antigen (GLURP);
human papilloma virus (HPV) antigen;
human papilloma virus HPV16 antigen;
HPV E5 protein;
HPV E6 protein;
HPV E7 protein;
a human immunodeficiency virus (HIV) antigen; and
an HIV gag antigen.
2. The nucleic acid molecule of claim 1 wherein the HSV is selected from the group consisting of HSV-1 and HSV-2.
3. The nucleic acid molecule of claim 2 wherein the first polypeptide segment comprises an amino acid sequence selected from the group consisting of:
(1) amino acids 26-265 of SEQ ID NO:27;
(2) amino acids 26-265 of SEQ ID NO:29;
(3) amino acids 1-244 of the glycoprotein D;
(4) amino acids 1-288 of the glycoprotein D; and
(5) amino acids 1-294 of a mature HSV glycoprotein D with the exception that amino acid 294 is alanine instead of tryptophan.
4. The nucleic acid molecule of claim 3 which comprises:
nucleotides 76-795 of SEQ ID NO:26; or
nucleotides 350-1069 of SEQ ID NO:28.
5. The nucleic acid molecule of claim 1 which encodes the amino acid sequence encoded by SEQ ID NO:35.
6. The nucleic acid molecule of claim 1 which comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:35; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:36; SEQ ID NO:37; and SEQ ID NO:34.
7. The nucleic acid molecule of claim 1 wherein the second polypeptide segment comprises the E5 protein, the E6 protein, and the E7 protein.
8. The nucleic acid molecule of claim 1 wherein the fusion protein comprises SEQ ID NO:23.
9. The nucleic acid molecule of claim 1 wherein the fusion protein comprises SEQ ID NO:22.
10. The nucleic acid molecule of claim 1 which comprises SEQ ID NO:32.
11. The nucleic acid molecule of claim 1 wherein the fusion protein comprises SEQ ID NO:33.
12. The nucleic acid molecule of claim 1 which is in a viral vector.
13. The nucleic acid molecule of claim 1 which is naked DNA.
14. The nucleic acid molecule of claim 1 which is in a bacterial vector.
15. The nucleic acid molecule of claim 1 wherein the third polypeptide segment comprises the transmembrane domain of the HSV glycoprotein D.
16. A fusion protein encoded by the nucleic acid molecule of claim 1 .
17. A method of inducing an immune response, comprising providing to a subject in need thereof a fusion protein of claim 16 .
18. The method of claim 17 wherein the fusion protein is provided by administering to the subject a nucleic acid molecule which encodes the fusion protein.