Targeted gene delivery to dendritic cells
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 delivering a lentivirus encoding a tumor antigen to elicit an antigen-specific cytotoxic T-cell response in a mammal comprising:
subcutaneously or intradermally 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 a tumor antigen, 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 antigen-specific cytotoxic T-cell response to the tumor antigen.
2. The method of claim 1 wherein the replication deficient lentivirus is administered subcutaneously.
3. The method of claim 1 wherein the E2 alphavirus glycoprotein is a Sindbis virus glycoprotein.
4. The method of claim 1 wherein the virus envelope further comprises an E1 alphavirus glycoprotein.
5. The method of claim 1 wherein the lentivirus comprises an HIV vector, a MSCV vector or an MLV vector.
6. The method of claim 1 wherein the tumor antigen is selected from the group consisting of MAGE, NY-ESO, tyrosinase, BAGE, RAGE, MART-1/Melan-A, gp100, gp75, mda-7, tyrosinase-related protein, prostate specific membrane antigen (PSMA), prostate-specific antigen (PSA), N-acetylglucosaminyltransferase-V, carcinoembryonic antigen, cytochrome P450 1B1, ras, Her2/neu, mutated ras, bcr/abl rearrangement, Her2/neu, mutated p53, wild-type p53, cytochrome P450 1B1, N-acetylglucosaminyltransferase-V, human papilloma virus protein E6, human papilloma virus protein E7, and alpha-fetoprotein.
7. The method of claim 1 wherein the replication deficient lentivirus further comprises a polynucleotide encoding a second antigen.
8. The method of claim 1 wherein the mammal is a human.