Investigating the MHC Class II-Restricted Processing Landscape of HIV-1 Antigens

Abstract

Robust HIV-specific CD4 T cell (TCD4+) responses are associated with decreased viral load, increased antibody neutralization breadth, and a slower progression to AIDS, and should therefore be considered in HIV vaccine development. TCD4+ are activated by antigen-derived peptides displayed in complex with MHCII on the surface of antigen presenting cells (APC). According to the classical model, internalized antigens are processed and loaded onto MHCII in late endosomal compartments. However, alternative mechanisms, such as endogenous processing, have been described. Endogenous processing occurs when virally-derived antigens produced within infected APCs are proteolyzed and loaded onto MHCII by a network of intracellular pathways. The contribution of these alternative processing pathways is not insignificant: our laboratory has shown that endogenous processing drives the vast majority of the in vivo TCD4+ response to influenza virus. The relative contributions of these pathways to the HIV-specific TCD4+ response, however, are unknown. Furthermore, our understanding of the cell types that act as APCs during HIV-1 infection is incomplete. For example, TCD4+, which transiently express MHCII and costimulatory molecules upon activation and are HIV host cells, might act in this capacity. To this end, we have assessed the processing and presentation capabilities of key cell types, including dendritic cells and macrophages. We observe significant heterogeneity in the processing of HIV-1 proteins by these cells. In addition, we found that activated TCD4+ express several components of the antigen processing machinery and are able to present antigen derived from a live HIV-1 infection. Future work is aimed at identifying the underlying machinery involved in this presentation, with the long-term goal of informing rational HIV-1 vaccine design.