HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently

Abstract

The ability of HIV-1-specific CD8+ T cell responses to recognize epitope variants resulting from viral sequence variation in vivo may affect the ease with which HIV-1 can escape T cell control and impact on the rate of disease progression in HIV-1-infected humans. Here, we studied the functional cross-reactivity of CD8 responses to HIV-1 epitopes restricted by HLA class I alleles associated with differential prognosis of infection. We show that the epitope-specific responses exhibiting the most efficient cross-recognition of amino acid-substituted variants were those strongly associated with delayed progression to disease. Not all epitopes restricted by the same HLA class I allele showed similar variant cross-recognition efficiency, consistent with the hypothesis that the reported associations between particular HLA class I alleles and rate of disease progression may be due to the quality of responses to certain “critical” epitopes. Irrespective of their efficiency of functional cross-recognition, CD8+ T cells of all HIV-1 epitope specificities examined showed focused TCR usage. Furthermore, interpatient variability in variant cross-reactivity correlated well with use of different dominant TCR Vβ families, suggesting that flexibility is not conferred by the overall clonal breadth of the response but instead by properties of the dominant TCR(s) used for epitope recognition. A better understanding of the features of T cell responses associated with long-term control of viral replication should facilitate rational vaccine design.

Fusion of a viral antigen to invariant chain leads to augmented T-cell immunity and improved protection in gene-gun DNA-vaccinated mice

“…However, preliminary studies using the adenoviral vector system indicate that much of the improved immunogenicity of the fused construct is preserved in MHC class II-deficient mice (Holst et al, unpublished observation), suggesting that increased MHC class I presentation represents a major mechanism underlying the remarkable efficiency of the fused construct. Interestingly, the response induced to LCMV GP covered a broad range of epitopes, both dominant and subdominant, which is important when attempting to control infections with rapidly mutating viruses, such as HIV (Frahm et al, 2006;Turnbull et al, 2006). Such a broad CD8 + T-cell memory response efficiently protected the vaccinated host against systemic infection with a high dose of virus, but the Ii-chain-based DNA vaccine did not prime for a substantial improvement in virus control following peripheral challenge.…”

MHC Class II-Associated Invariant Chain Linkage of Antigen Dramatically Improves Cell-Mediated Immunity Induced by Adenovirus Vaccines

“…Thus, it seems safe to conclude that adenovirus vaccines expressing Ii-linked Ags may be used successfully in situations where unmodified vaccines have failed. In particular, the ability to induce protective immunity from subdominant epitopes, which we have verified for both the LCMV glycoprotein and NP, could be relevant for mutating and highly variable viruses like HCV and HIV (33,34). Even if a protective HIV or HCV vaccine remains elusive, at the very least, the strategy described should be applicable to make improved protective vaccines for the related arenaviruses Lassa, Junin, Sabia, Machupo, and Guanorito which infect humans with high case-fatality rates, or the filoviruses Ebola and Marburg toward which unmodified adenovirus vaccines have already proved effective (35)(36)(37)(38).…”

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

“…Changes in CTL specificity could lead to the accumulation of less effective antiviral CTLs in the late chronic phase of an infection (6,11,12). There are a number of different possibilities in the literature that potentially explain the heterogeneity in the antiviral activity of CTLs, such as: differences in functional avidity of CTLs toward exogenously pulsed synthetic peptides (7,13), TCR usage (14,15), cross-reactive capacity of CTLs toward variant Ags (14,16), kinetics and amplitude of immunogenic protein expression (9,(17)(18)(19), Ag processing and presentation pathways (20,21), and binding activity of an antigenic peptide to a given HLA class I molecule (22). However, considering that immunodominant peptides are not always those with the highest density presented at the target cell surface (23,24) and that immunodominant CTLs are not always correlated with effective antiviral CTL responses (25), an interesting question can be raised as to whether, and if so what, inherent characteristics of target epitope peptides support the efficient recognition by CTLs for the killing of virus-infected cells.…”