Selective targeting of HIV infected clones by cognate peptide stimulation and antiproliferative drugs

Clonal expansion of HIV infected CD4+ T cells is a barrier to HIV eradication. We previously described a marked reduction in the frequency of the most clonally expanded infected CD4+ T cells in an individual with elite control (ES24) after initiating chemoradiation for metastatic lung cancer with a regimen that included paclitaxel and carboplatin. We tested the hypothesis that this phenomenon was due to a higher susceptibility to the chemotherapeutic drugs of CD4+ T cell clones that were sustained by active proliferation. We studied a CD4+ T cell clone with replication-competent provirus integrated into the ZNF721/ABCA11P genes, termed ZNF721i. We stimulated the clone with its cognate peptide and then exposed the cells to paclitaxel and/or carboplatin or the antiproliferative drug, mycophenolate mofetil. While treatment of cells with the cognate peptide alone led to a marked expansion of the ZNF721i clone, treatment with the cognate peptide followed by culture with either paclitaxel or mycophenolate mofetil abrogated this process. The drugs did not affect the proliferation of other CD4+ T cell clones that were not specific for the cognate peptide. This strategy of antigen-specific stimulation followed by treatment with an antiproliferative agent may lead to the selective elimination of clonally expanded HIV-infected cells. PBMCs were cultured with peptides 42 and 61 for 20 hours and then washed and cultured as described above. On day 4, paclitaxel (58nM) was added and on day 7, CD4 isolation was performed on these samples and on freshly obtained PBMCs. An annexin V column was used to remove dead cells. ES24_1 corresponds to cells non stimulated (DMSO) and treated with DMSO on day 4. ES24_2 corresponds to cells non stimulated (DMSO) and treated with paclitaxel on day 4. ES24_3 corresponds to cells stimulated with gag peptides and treated with paclitaxel on day 4. ES24_4 corresponds to cells stimulated with gag peptides and treated with DMSO on day 4. ES24_5 corresponds to CD4s freshly isolated from uncultured PBMCs. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************