Recognition of Variant HIV-1 Epitopes from Diverse Viral Subtypes by Vaccine-Induced CTL

Abstract

Recognition by CD8+ T lymphocytes (CTL) of epitopes that are derived from conserved gene products, such as Gag and Pol, is well documented and conceptually supports the development of epitope-based vaccines for use against diverse HIV-1 subtypes. However, many CTL epitopes from highly conserved regions within the HIV-1 genome are highly variable, when assessed by comparison of amino acid sequences. The TCR is somewhat promiscuous with respect to peptide binding, and, as such, CTL can often recognize related epitopes. In these studies, we evaluated CTL recognition of five sets of variant HIV-1 epitopes restricted to HLA-A*0201 and HLA-A*1101 using HLA transgenic mice. We found that numerous different amino acid substitutions can be introduced into epitopes without abrogating their recognition by CTL. Based on our findings, we constructed an algorithm to predict those CTL epitopes capable of inducing responses in the HLA transgenic mice to the greatest numbers of variant epitopes. Similarity of CTL specificity for variant epitopes was demonstrated for humans using PBMC from HIV-1-infected individuals and CTL lines produced in vitro using PBMC from HIV-1-uninfected donors. We believe the ability to predict CTL epitope immunogenicity and recognition patterns of variant epitopes can be useful for designing vaccines against multiple subtypes and circulating recombinant forms of HIV-1.

Broad Cross-Clade T-Cell Responses to Gag in Individuals Infected with Human Immunodeficiency Virus Type 1 Non-B Clades (A to G): Importance of HLA Anchor Residue Conservation

“…In addition, we could identify additional epitopes that are in part responsible for the cross-clade T-cell responses observed in our study by using HLA motif-finding algorithms. Although it is known that HLA motif prediction can miss in vivo-responsive CTL epitopes (23), a bioinformatics approach has proven to correlate with in vivo findings (13,21,45,58). In total, 25% (6/24) of the positive Gag pools in our study could be linked with previously documented cross-clade-responding epitopes in non-clade B-infected patients.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…All 10 VP13/14 epitopes shared the HLA-A*02:01-binding motifs: leucine or valine at the second position and a leucine, valine, methionine, or alanine at the ninth position. On the basis of the computational algorithms listed above, these VP13/14 epitopes bear putative antigenic and immunogenic HLA-A*02:01-binding regions and thus are more likely to be less constrained than other parts of the VP13/14 molecule, resulting in increased accessibility to proteolysis, an event that precedes T-cell epitope presentation in association with an HLA molecule (30)(31)(32)(33)(34)(35).…”

The Antiviral Efficacy of Simian Immunodeficiency Virus-Specific CD8 + T Cells Is Unrelated to Epitope Specificity and Is Abrogated by Viral Escape

“…Recent studies of HIV have observed the ability of antigen-specific CD8 ϩ T lymphocytes to recognize variant peptides by using gamma interferon (IFN-␥) production as the readout, providing encouragement that the immune system may be able to cope with viral escape (22,24,46,64). Similarly, we detected cytokine responses to a variant Gag peptide in both IFN-␥ enzyme-linked immunospot (ELISPOT) and IFN-␥/tumor necrosis factor alpha (TNF-␣) intracellularcytokine-staining (ICS) assays.…”