T Cell Receptor Recognition Motifs Govern Immune Escape Patterns in Acute SIV Infection

Abstract

Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural configuration of constituent TCR clonotypes within virus-specific CD8(+) T cell populations. Analysis of 3416 SIV-specific TCR sequences revealed that polyclonal T cell populations characterized by highly conserved TCRB CDR3 motifs were rendered ineffectual by single residue mutations in the cognate viral epitope. Conversely, diverse clonotypic repertoires without discernible motifs were not associated with viral escape. Thus, fundamental differences in the mode of antigen engagement direct the pattern of adaptive viral evolution. These findings have profound implications for the development of vaccines that elicit T cell immunity to combat pathogens with unstable genomes.

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

“…These findings have important implications for designing vaccines aimed at promoting the magnitude and breadth of what are normally "minor" responses. This, in turn, may be advantageous for efficient viral clearance as well as the prevention of viral escape (4,5,53). The same arguments may apply to tumor immunity.…”

“…While much of the research focus has been on the more readily analyzed large, dominant CTL populations, it has become apparent that subdominant responses can also play a key role in immunity (2), particularly in situations where a diverse array of "minor" epitopes is being recognized (2,3) or there is the potential for mutational escape from immune control. Given that protection and recovery from any given virus infection is likely to depend on the overall breadth and extent of immunity (2)(3)(4)(5), developing a better understanding of factors that determine CTL immune magnitude is essential, particularly for the design of novel vaccination and immunotherapy strategies that make optimal use of subdominant CTL responses.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…This phenomenon clearly requires ongoing antigen-specific CD8 + T-cell function but whether or not this selection can only be mediated by T-cells with a normal effector phenotype or how much T-cells with an exhausted phenotype could be involved remains unclear. Nonetheless, the late occurring appearance of mutant viruses in established chronic infection is a fundamental indicator for long-term maintenance of functional T-cell responses and highlights that exhausted T-cell populations possibly contribute to select escape variants 26,27 . The association between the late emergence of escape mutations, concomitant steep viral load increase, and disease progression to AIDS in HIV infections underline the aforementioned considerations.…”

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

“…Fluorochrome-conjugated tetrameric Mamu-A*01 complexes were used to label cognate CD8 ϩ T cell populations specific for the CM9 (CTPY DINQM; Gag, residues 181-189) epitope as described previously (55). Viable Ag-specific CD8 ϩ T cells were then isolated by flow cytometric sorting to Ͼ99% purity and extracted mRNA was subjected to a template switch-anchored RT-PCR that amplifies all expressed TCRB gene products without bias; resultant products were subcloned, sequenced, and analyzed as described previously (55) to generate a comprehensive picture of clonal representation within each CM9-specific CD8 ϩ T cell population.…”

“…To assess the effects of IL-7 and IL-15 on the clonotypic composition of SIV epitope-specific CD8 ϩ T cell responses, we sorted viable CM9-Mamu-A*01 tetramer ϩ CD8 ϩ T cells from MHC class I allele-matched macaques in groups 4, 5, and 6 to Ͼ99% purity and conducted a longitudinal molecular analysis of constituent clonotypes using an unbiased template switch-anchored RT-PCR as described previously (55). There was a significant decrease in overall clonality across the cohort after 4 wk of ART before vaccination (week 20) compared with a postprimary infection pretreatment time point (week 12) ( p ϭ 0.0312); upon the subsequent cessation of ART after immune manipulation (week 41), no significant changes in clonality were observed (Fig.…”