TCR recognition is a mediator in the control of HIV infection by CD8 T cells

Abstract

Abstract CD8 T cell responses to HIV-specific MHC class I epitopes are critical for the control of HIV infection. The precise mechanisms that govern the control of HIV by CD8 T cells are largely unknown. Certain protective HLA alleles, such as, B*5701, are associated with long-term control of HIV-1. However, other mechanisms by CD8 T cells might be contributing to the control of HIV, because non-controllers with these protective alleles have been reported. Therefore, to determine the molecular mechanisms that underlie HIV control by CD8 T cells we assembled a cohort of HIV positive individuals, which consisted of controllers (viral load less than 2000 copies per mL), ART-naive non-controllers, and non-controllers on ART-therapy. Using PBMCs from our cohort we first stained the cells with a panel of thirteen T cell markers and then performed polychromatic single cell index sorting of CD3+CD8+ MHC class I tetramer-binding cells. Our tetramers consisted of HIV epitopes bound to HLA-B*5701, A*0201, B*0702 or B*0801. We then determined the TCR diversity for each tetramer-binding population by single cell TCR sequencing. We also reconstructed HIV-specific TCRs and expressed them in a reporter T cell line to measure TCR avidity to the tetramer. We found that HIV controllers have: (1) a diverse TCR repertoire for the KF11 epitope presented by B*5701, in contrast, to non-B*5701 alleles presenting HIV epitopes that are heavily skewed; (2) high avidity HIV-specific TCRs for HIV epitopes presented by B*5701; and (3) TCR-expanded clones with a novel CD27dimCD45ROneg T cell phenotype. Importantly, lack of any three of these parameters resulted in the inability to control HIV, indicating that no single parameter is sufficient for natural control.