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Background HIV-specific CD8 T cells responses rely on the recognition of peptide-MHC-I complexes by cognate T cell receptors. HIV-derived MHC-I epitopes result from the degradation of viral proteins by the cellular processing machinery including proteasomes and aminopeptidases. Interferon gamma changes proteasome composition and peptidase activities. We hypothesize that HIV infection might affect the expression or activities of the antigen processing machinery, either through a direct effect of the virus or indirectly through cellular activation or from the release of cytokines by surrounding infected cells.

Background Whether HIV-infectable subsets, such as CD4 T cells, monocytes, macrophages and dendritic cells (DCs), have equivalent capacity to produce and present MHC-I restricted epitopes to HIV-specific CD8 T cells is unknown. MHC-I epitopes are processed by an intracellular degradation pathway involving multiple proteases. In this study we analyzed the effect of toll-like receptor (TLR) agonist-mediated maturation on the processing and presentation of HIV antigens in monocyte-derived DCs and macrophages.

Background Epitopes displayed by MHC-I come from the multistep degradation of proteins by intracellular peptidases such as proteasome and aminopeptidases or cathepsins in the exogenous pathway. We hypothesize that due to structural homologies HIV protease inhibitors (PIs) used in antiretroviral therapies may affect activities of cellular peptidases involved in epitope processing and may affect epitope presentation to immune cells. Methods Using a fluorogenic assay the effect of 5 HIV-1 PIs (Ritonavir, Saquinavir, Nelfinavir, Indinavir, Atazanavir) on proteasome, aminopeptidase and cathepsin activities was tested in PBMCs from at least 6 healthy donors. Using PBMC cytosol as a source of peptidases and HPLC and mass spectrometry to define and quantify the degradation products, the effect of HIV PIs on HIV peptide processing kinetics and HIV epitope half-life was assessed. Finally we assessed the impact of PIs on the endogenous processing and presentation of epitopes by infected cells to CD8 T cells using a fluorescence-based cytotoxicity assay. Results HIV PIs variably altered proteasome, post-proteasomal aminopeptidases and cathepsin activities. Depending on the PI, some activities were inhibited (from 1.1 to 5 folds, p

Background HIV-1 Nef is a multifunctional protein frequently targeted by host CD8+ T cell responses in early and chronic phases of HIV-1 infection. In vivo reversions of CTL escape mutations within Nef have been reported, suggesting a possible impact of immune-selected mutations in Nef on viral fitness. The goal of this work was to determine whether CD8+ T cell selected mutations in regions outside of Gag, such as in Nef, also impair viral replication and may thus contribute to early immune control of HIV-1.