Control of M184V HIV-1 mutants by CD8 T-cell responses

Abstract

Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug-resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A*02:01-YQYVDDLYV and A*02:01-VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies.

Comparison of experimental fine‐mapping to in silico prediction results of HIV‐1 epitopes reveals ongoing need for mapping experiments

“…22 Interferon-c ELISPOT HIV-1-specific CD8 T-cell responses and CD8 T-cell epitope mapping were evaluated partly within different projects. 23,24 HIV-specific CD8 T-cell responses were quantified by ELISPOT assay using fresh or frozen PBMC (0Á5 9 10 5 to 1 9 10 5 per well) and peptides (final concentration 12Á5 lg/ml) as described previously. 25,26 Interferon-c-producing cells were counted by direct visualization on an AID Elispot Reader (Autoimmun Diagnostika GmbH, Strassberg, Germany) and were expressed as spot-forming cells (SFC) per 10 6 PBMC.…”

Potential Elucidation of a Novel CTL Epitope in HIV-1 Protease by the Protease Inhibitor Resistance Mutation L90M

“…To be thorough, A*02 was tested for negative correlation with an RT mutation that confers resistance against emtricitabine, abacavir and lamivudine, M184V. The mutation causes an increase in immunogenicity of an A*02 epitope spanning RT 181–189, YQYMDDLYV (Y9V) [38]. Sequence sets were divided based on the presence or absence of the mutation M184V, much like The sequence sets were divided based on the presence or absence of the M184V mutation.…”

Vaccination against infectious diseases: What is promising?

“…Albeit biggest labour no efficacious vaccination could be produced up to date [5]. However, pathogenic research is in progress looking for measures to enhance the cellular-mediated immune response [66][67][68][69][70][71].…”