Vaccination against drug-resistant HIV

Abstract

As the use of antiretroviral drug treatment increases worldwide, development of drug resistant HIV phenotypes is expected to increase. The frequency of drug- or multi-drug resistant virus transmitted in primary infections will consequently be more abundant. Logical vaccine targets in drug-resistant strains are reverse transcriptase and protease. However, even though antibodies and cell-mediated responses can be seen in patients, it has been difficult to develop highly immunogenic vaccines against RT in animal models. This motivated novel strategies to increase immunogenicity of current RT and PR immunogens.

We have focused our efforts to stimulate the immunogenicity of HIV reverse transcriptase and protease by three different approaches. First, we have selected specific epitopes of the two proteins, where drug-resistant mutations are known to take place, and investigated how well these can stimulate an immune response to the entire protein. Secondly, DNA vaccine constructs encoding full-length reverse transcriptase were created from multi-drug resistant primary isolates and tested as vaccine candidates. Thirdly, we enhance the immune presentation of the proteins by modifying the processing pathway of the protein and we hope by that to increase the immunogenicity of the protein.

Most of the selected epitopes (both wild type and mutant analogs to those) were found to be immunogenic in mice. The epitopes were immunogenicity as peptides and when they were expressed in multi-CTL epitope DNA constructs. Wild type full-length RT gene expressed as DNA plasmid were weakly immunogenic, whereas a multidrug resistant mutant did not stimulate an immune response. The difference in expression and intracellular processing found between the different constructs and gene product may partly explain this.

Furthermore, screening to find naturally immunogenic sites in RT and PR in HIV-1 infected patients is ongoing. The result from these studies may help us to pick out sites in the proteins that are naturally immunogenic and to which potential vacci ne can be targeted. This may enhance the pre-existing immunity to those regions. Immunogenicity studies of the effect of fusing RT with ornithine decarboxylase are planned. We are also investigating the efficiency of coupling vaccines to erythrocytes and using these cells as carriers of the vaccine to antigen presenting cells. These studies look into the possible advantages in using drug-induced variants of the wild type epitopes as a way to suppress the development of drug resistance.