Targeted gene delivery for dendritic cell vaccination
Methods and compositions are provided for delivery of a polynucleotide encoding a gene of interest, typically an antigen, to a dendritic cell (DC). The virus envelope comprises a DC-SIGN specific targeting molecule. The methods and related compositions can be used to treat patients suffering from a wide range of conditions, including infection, such as HIV/AIDS, and various types of cancers.
1. A method of eliciting an antibody response or antigen-specific T-cell response in a mammal comprising:
administering to said mammal a replication deficient lentivirus pseudotyped with a virus envelope comprising a modified E2 alphavirus glycoprotein comprising a modification that reduces binding of said E2 to heparan sulfate, wherein the lentivirus comprises a polynucleotide encoding an antigen wherein said polynucleotide is exogenous to the lentivirus genome, and wherein the lentivirus comprising the modified E2 alphavirus glycoprotein more efficiently transduces dendritic cells expressing DC-SIGN relative to cell types not expressing DC-SIGN, in an amount sufficient to elicit an antibody response or antigen-specific T-cell response to the antigen.
2. The method of claim 1 wherein the administering elicits an antigen-specific T-cell response.
3. The method of claim 2 wherein the administering elicits an antibody response.
4. The method of claim 2 wherein the replication deficient lentivirus is administered subcutaneously.
5. The method of claim 1 wherein the E2 alphavirus glycoprotein is a Sindbis virus glycoprotein.
6. The method of claim 5 wherein the administering elicits an antigen-specific T-cell response.
7. The method of claim 5 wherein the administering elicits an antibody response.
8. The method of claim 1 wherein the replication deficient lentivirus is administered subcutaneously.
9. The method of claim 5 wherein the replication deficient lentivirus is administered subcutaneously.
10. The method of claim 5 wherein the virus envelope further comprises an E1 alphavirus glycoprotein.
11. The method of claim 1 wherein the E2 glycoprotein is produced from the nucleic acid sequence of SEQ ID NO: 3 or comprises the amino acid sequence of SEQ ID NO: 11.
12. The method of claim 5 wherein the lentivirus comprises an HIV sector, a MSCV vector or an MLV vector.
13. The method of claim 1 wherein the replication deficient lentivirus further comprises a polynucleotide encoding a second antigen.
14. The method of claim 5 whereint he replication deficient lentivirus further comprises a polynucleotide encoding a second antigen.
15. The method of claim 5 whereint he mammal is a human.
16. The method of claim 1 wherein the antigen is a tumor associated antigen, viral antigen, bacterial antigen, fungal antigen, protozoan parasite antigen, helminth parasite antigen, or ectoparasite antigen.
17. The method of claim 2 wherein the antigen- specific T-cell response is a CD8* T-cell response.