Identification of novel CD4 and CD8 T cell epitopes for targeting in HIV-1 vaccine design

Keywords: Proteomics, Immunology, Virology.
Development of vaccines to combat infection with human immunodeficiency virus type 1 (HIV-1) is challenging, as the virus possesses multiple immune evasion strategies that enable it to persist in all individuals who develop systemic infection. Novel, rationally-designed vaccine strategies are thus required to elicit responses that are more efficacious than those naturally induced during infection. Two complementary approaches for prophylactic HIV-1 vaccine development entail induction of broadly-neutralising antibody (bnAb) responses to block the establishment of infection, and induction of CD8 T cell responses to eradicate virus early after infection and prevent long-term persistent infection. CD8 T cell-based vaccines also have potential therapeutic utility in individuals chronically infected with HIV-1.
Analysis of features of CD8 T cell responses associated with good control of viremia in HIV-1-infected individuals suggests that targeting of Gag-derived epitopes that are rapidly presented on infected cells (prior to major histocompatibility complex (MHC) downregulation); and targeting of epitopes in conserved viral sequences where escape incurs high costs to virus fitness, together with induction of co-dominant responses to a breadth of epitopes to minimise viral mutational escape, are beneficial (reviewed by McMichael et al, 2010). Similarly the only T cell-inducing vaccine shown in preclinical models to enable ~50% of vaccinated animals to eradicate infection following virus challenge was found to have induced a tremendous breadth of CD8 T cell responses that, unusually, targeted epitopes restricted by the non-classical class I molecule MHC-E and by MHC class II, which are not down-regulated on infected cells (Hansen et al, 2013, 2016).
Recent advances in mass spectrometry (MS) technology now enable application of MS-based approaches for interrogation of the MHC-bound immunopeptidome of cell lines or primary cells (Croft et al, 2015). Using this technique to assess the repertoire of peptides presented with MHC class I on HIV-infected primary CD4 T cells, we recently identified not only peptides derived from the conventional viral open reading frames and cryptic epitopes (Ternette et al, 2016), but also novel peptides derived from the HIV-1 5' leader sequence, which was previously not thought to be translated (unpublished data). The first aim of this project will be to extend this work, aiming i. to identify post-translationally-modified HIV-1 peptides presented on HIV-infected cells; ii. to identify viral peptides presented very rapidly following infection of cells with HIV; iii. to compare the repertoire of self peptides presented on HIV-infected and uninfected cells to gain insight into self ligands available for recognition by T or natural killer (NK) cells; and iv. to use an in vitro HIV latency model to assess the repertoire of HIV and self peptides presented on latently infected cells. Follow-on studies will address whether T cell responses are elicited during HIV infection to novel epitopes identified by MS. T cell lines/clones that recognise novel epitopes will also be generated and their antiviral efficacy evaluated in in vitro models of productive and latent HIV infection to give insight into the utility of targeting these epitopes in HIV CD8 T cell vaccine design.