TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

Abstract

Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease progression, yet most persons expressing these alleles are unable to control HIV-1. Here we show that HLA-B*27-restricted CD8+ T cells in controllers and progressors differ in their ability to inhibit virus replication through targeting of the immunodominant Gag epitope. This is associated with distinct TCR clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity against epitope variants, and enhanced perforin delivery. Clonotype-specific differences in antiviral efficacy were also observed for an immunodominant HLA-B*57 restricted response in controllers and progressors. Thus, the efficacy of protective alleles is modulated by specific TCR clonotypes selected in natural infection, providing a functional explanation for divergent HIV-1 outcomes.

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Furthermore, special thymic selection inducing a larger B27-driven CD8 1 T cell precursor repertoire, preferential usage of certain T cell receptor (TCR) clonotypes associated with higher cross-reactive and, finally, better capacity of evasion from regulatory T cell (T reg )-mediated suppression have also been documented [55][56][57][58].…”

Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations

“…In addition, both central memory (19) and effector memory (20,21) phenotypes have been associated with viremic control, particularly in the absence of negative regulation (22)(23)(24)(25). More recently, the clonotypic composition of HIV-specific CD8 T cell populations has also emerged as a key correlate of immune control (26,27). These properties are interlinked and reciprocally affected by viral load, but nonetheless serve as guides to inform further studies (28)(29)(30).…”

Differential Potency and Breadth of the Same Epitope-Specific CTLs to Inhibit HIV-1 Replication based on TCR Usage

“…This approach incorporates numerous steps that influence virus replication in vivo, including viral entry, antigen processing, epitope presentation, epitope recognition by CD8 T cells, infected cell lysis, and subsequent spread of infection to uninfected cells. We have further demonstrated that TCR clonotypes modulate CTL function against HIV-1 infection by lytic granule loading and delivery after TCR and HLA/peptide engagement [23]. Our current data, employing the viral inhibition assay that measures the relative antiviral efficacy of multiple CTL clones specific for the same epitope from the same HIV-1 infected subject, indicate differential antiviral efficacy of CTL clones due to the distinct TCR usage and ability to produce MIP-1β.…”