Impact of HLA-B Alleles, Epitope Binding Affinity, Functional Avidity, and Viral Coinfection on the Immunodominance of Virus-Specific CTL Responses

Abstract

Immunodominance is variably used to describe either the most frequently detectable response among tested individuals or the strongest response within a single individual, yet factors determining either inter- or intraindividual immunodominance are still poorly understood. More than 90 individuals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.

A Quantitative Analysis of the Variables Affecting the Repertoire of T Cell Specificities Recognized after Vaccinia Virus Infection

“…We are currently investigating whether the nonimmunogenicity of roughly 50% of the high-affinity binders is due to homology with host proteins (which might have led to negative selection) by comparing the peptide sequences against the mouse proteome. A high functional TCR avidity has also been shown to be associated with high-magnitude responses (63). However, with the data generated in the avidity experiments, there was no clear correlation (or inverse correlation) between the magnitude of particular epitopespecific CD8 ϩ T cells and avidity.…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…Plates were developed with Mabtech reagents (Mabtech). Half-maximal stimulatory Ag doses (SD 50 ) were determined as the peptide concentration needed to achieve a half-maximal number of spots in the ELISPOT (54). Thresholds for positive responses were determined as at least five spots (50 sfc/10 6 ) per well and responses exceeding a mean of negative wells plus 3 SDs.…”

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

“…Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4,5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6,7).…”