The HLA Class I Restricted CTL Response in HIV-1 Infection: Systematic Identification of Optimal Epitopes
Christian Brander1 and Bruce D. Walker2
1AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Room 5234, Charlestown, MA 02129, USA, and
2Harvard Medical School Boston, MA USA
I. Introduction
Viral infection induces CD8+ cytotoxic T lymphocytes (CTL) responses by presenting viral antigen on MHC class I molecules at the surface of infected cells(1).1 A vigorous CTL response is also associated with Human Immunodeficiency Virus (HIV) infection (2).2 HIV specific CTL are thought to play an important role in the control of the virus during clinical latency and may influence the course of disease development (3-6).3 Furthermore, experiments in HIV-exposed, uninfected individuals suggest that CTL could provide protection from infection (7-9).7 The characterization of the antigenic epitopes involved in CTL induction is important not only for a better understanding of disease pathogenesis, but also for possible vaccine development. Since the first description of HIV specific CTL, the efforts of many laboratories have led to the identification of a large number of epitopes involved in the HIV-1 specific CTL response in infected persons(10, 11).10;11 A summary of those sequences is accessible in this database. It contains more than 200 peptides, which contain putative HLA class I restricted epitopes. In many cases, these peptides require further definition as to the minimal epitope or the restricting HLA molecule. Here, we have compiled a list of peptides that have been defined in terms of the minimal length that mediates the most effective target cell sensitization in the context of the restricting class I molecule. More than 60 peptides fulfilling these criteria were included in the last database update (11).11 Within the last 12 months, more than 30 new optimal epitopes have been identified, many of which are not yet published or are in submitted reports.
II. Presentation and recognition of viral antigen on MHC class I
Recent advances in the understanding of MHC class I antigen processing have provided insights into peptide selection for CTL responses. Viral antigen is presented to specific T cells as short peptides in association with MHC molecules (1, 12).1;12 These antigenic epitopes are derived from viral cytosolic proteins which undergo proteasome mediated processing (3, 13).3;13 A number of parameters likely influence peptide processing, including amino acids both within and outside the CTL epitope in the cytosol(14).14 Following processing, the peptides are translocated into the lumen of the ER by the TAP1/TAP2 heterodimer and bound to nascent MHC class I molecules. Both interactions (TAP and MHC) seem to have restrictive specificities and to allow only some peptides to be presented (3, 13, 15).3;13;15 Whereas peptide binding to MHC molecules has been extensively studied, both the impact of different TAP-alleles on the generation of peptides and the link between TAP alleles and HLA alleles are unclear (15-17).15 As revealed by peptide titration studies and peptide elution from the isolated MHC class I molecule, HLA class I restricted epitopes normally are about 8-12 amino acids in length and have certain anchor residues to bind into specific pockets of the MHC class I molecule. These pockets, designated A, B, C, D, E and F, are located in the antigen binding site on the class I molecule formed by two alpha helices, with the floor of the groove formed by a beta-sheet structure (18).18 As the pockets are located at the edge of the peptide binding groove, the anchor positions in the peptides are often in positions 1, 2 and 9 of the processed peptide (19).19 However, other residues can influence the peptide binding as well (20).20 Eluting peptides from various MHC class I molecules has led to the definition of MHC-allele-specific binding motifs (19-21).19; These motifs can be used to screen protein sequences in order to find potentially antigenic epitopes presented by a certain HLA allele (22).22 However, this approach only reflects peptide binding but not necessarily their involvement in the natural CTL response in vivo, as such evaluations do not analyze the effects of protein processing and transportation. Very recently, the x-ray crystal structure and orientation of a T cell receptor (TCR) bound to a MHC/peptide complex was described (23).23 The V region of the alpha and the beta chains, resembling antibody structures, contacts the presented peptide in its core region through the third complementarity-determining regions (CDR 3), forming a deep hydrophobic cavity. The CDR1 and CDR2 regions of the alpha-chain appear to contact the MHC/peptide complex around the N-terminal end of the embedded peptide, whereas the beta chain CDR1 and CDR2 contact the C-terminus of the peptide. These findings may help to explain the biased use of certain V-beta chain segments observed in various immune responses, i.e. influenza infection and different autoimmune diseases (24, 25).25;24
III. Identification of HIV-1 derived CTL epitopes
Various methods have been used to identify HIV-1-derived, HLA class I restricted epitopes. The majority of epitopes have been defined using CTL lines or clones recognizing recombinant viral antigen, such as target cells infected with vaccinia virus constructs expressing selected HIV-1 proteins. The minimal epitope for these responses is determined by using synthetic peptides, followed by titration assays with truncated peptides to identify the optimal epitope (26).26 Alternatively, binding-motif based searches for potential epitopes has led to the identification of some optimal epitopes (22).22 However, to prove that the binding peptide is involved in the natural immune response to HIV, recognition of the naturally processed peptide by CTL in infected persons is required. Finally, elution of peptide from HLA class I molecules allows for the direct isolation of processed, class I binding epitopes (27).27 However, these epitopes are not necessarily immunogenic in vivo and may thus not induce a CTL response in infected humans.
In published studies, different methods have been used to identify optimal
epitopes. In some cases the HLA restriction has not been shown or the
optimal epitope has not been defined by titration assays using truncated
peptides. The Los Alamos HIV Molecular Immunology Database contains all
reported sequences with CTL activity, regardless of their definition as optimal
epitopes. However, for many different questions and approaches such as the
design of a epitope based vaccine, the knowledge of the optimal epitope is a
prerequisite. In the list presented here (Table 1), we include only those
peptides which fit rigid criteria: 1) the CTL recognize the naturally
processed epitope, 2) titration assays with truncated peptides have
identified the optimal epitope and 3) the restricting HLA molecule has been
defined. A number of likely optimal epitopes were not included as these
criteria were not met. For example, we did not include putative HLA-Cw8
restricted epitopes, since Cw8 is in a strong linkage disequilibrium with
HLA-B14 and it is thus difficult to identify the restricting HLA allele by
using (mis)matched cell lines (28, 29).28;29 However, these sequences can be
found in other parts of the database.
IV. Analysis of HIV-1 derived CTL epitopes
The list of HIV derived CTL epitopes will continue to grow, as new epitopes are found and longer sequences are mapped to the optimal epitope. The list given in Table 1 should provide investigators with a reliable compilation of optimal CTL epitopes in HIV. With the growing number of defined optimal epitopes, some interesting characteristics are beginning to emerge. More epitopes which overlap with previously described ones have been identified, as have epitopes which can be restricted by multiple HLA alleles. These latter epitopes could be interesting candidates for peptide based vaccine development. This is the case for RT protein derived epitope AIFQSSMTK (a.a.325- a.a.333) which binds to HLA-A3 and HLA-A11, both members of the same binding motif superfamily (30).30 The gag-p17 derived peptide RLRPGGKKKY (a.a. 20-29) was found to be presented by at least three different HLA alleles (HLA-A3, -B42, -Bw62). Additional examples of epitopes binding to multiple HLA molecules are included in this list and can be conveniently found by searching the Los Alamos Database. Furthermore, it becomes clear that some areas contain multiple overlapping peptides. By minute alteration (i.e. truncation by or substitution of one amino acid), those epitopes may be able to bind to additional HLA molecules without losing the binding affinity to the original HLA molecule(s) nor escaping recognition by CTL specific for the original peptide. Different studies have shown that there can be wide cross recognition of variants of certain epitopes (8, 31, 32).8;31;32 This would suggest that a less conserved, but highly immunodominant epitope may serve as a superior immunogen for vaccine development than one which is highly conserved, but only rarely recognized. However, one must consider the potential adverse effects of sequence variation within, or flanking, these epitopes which may alter peptide processing and presentation. In general, it seems that the induction of a strong CTL response requires epitopes that bind tightly to the class I molecule. It has been suggested that the immunogenicity of potential CTL epitopes can be predicted more accurately by the dissociation rate than by the binding affinity (33).33 Although Table 1 lists numerous epitopes, little is known about their potential immunodominance, which may be especially important with regard to the development of peptide based vaccines (32, 34).32;34 The mechanisms leading to such immunodominance are not clear, although several reasons have been discussed. These include the preferential processing of certain epitopes by the proteasome due to favored flanking regions, the binding affinity to the class I molecule, the peptide selectivity of the TAP dimer, and a lack in the T cell repertoire. Thus, epitopes selected as peptide vaccine candidates may need to be tested not only for variability and binding affinities but rather for parameters like dissociation rate and immunodominance.
Acknowledgments
We would like to thank all the investigators who contributed unpublished data for inclusion in this list and in the Los Alamos HIV Molecular Immunology Database. This work was supported by the Schweizerische Stiftung fuer Medizinisch Biologische Stipendien, the Swiss National Foundation, NIH grants A128568 and A130914, and by a grant from the Pediatric AIDS Foundation (ARIEL Project for the prevention of HIV-transmission from mother to infant).
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