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Much of the current effort in HIV-1 vaccine design is directed at achieving T-cell immunity that will result in enough immunological memory to contain HIV-1 infection after acquisition. However, antigenic diversity, plus a lack of understanding of HIV-1 vaccine immunology, have hindered the development of a globally effective cytotoxic T-lymphocyte (CTL)-based vaccine. Cellular response, in using a finite immune system to recognize an infinite number of potential pathogens, exhibits a series of parsimonious features. These features are considered critical in modulating HIV-1 vaccine multiple specificities. We took the features into consideration when the potential epitope coverage (E(c)) to circulating strains by current vaccine strategies was analyzed. Based on these analyses, several approaches are proposed to enhance the breadth of vaccine responses and, hence, the potential protective efficacy.

Dozens of human immunodeficiency virus-type 1 (HIV-1) vaccine candidates specifically designed to elicit cytotoxic T-lymphocyte (CTL) responses have entered the pipeline of clinical trials. Evaluating the immunogenicity and potential efficacy of these HIV-1 vaccine candidates is challenging in the face of the extensive viral genetic diversity of circulating strains. Standardized peptide reagents to define the magnitude and potential breadth of the T-cell response, especially to circulating strains of HIV-1, are needed. For this purpose we developed a biometric approach based on T-cell recognition pattern for defining standardized reagents. Circulating strains in the Los Alamos database were evaluated and standardized algorithms to define all potential T-cell epitopes (PTEs) were generated. While many unique PTEs could be identified, a finite number based upon prevalence of circulating strains in the database, which we define as vaccine-important PTEs (VIPs), were used to select a common standardized panel of HIV-1 peptides for CTL-based vaccine evaluation. The usability of PTE peptide set was manifested by detection of Nef-specific CTL responses in HIV-1 subtype B infections.

The cellular immune system is characterized by flexibility with respect to epitope recognition at the level of peptide binding to HLA molecules and HLA-peptide complexes to T-cell receptors (TCRs). For epitopes recognized by cytotoxic T-lymphocytes (CTLs), amino acid substitutions at different positions have varying impact on recognition. By analyzing the frequencies of specific amino acid substitutions at each position in conjunction with HLA-peptide binding and immune-response data, we have developed new methods to predict cross-reactive recognition of epitope variants by CTLs. We derived position-specific substitution matrices (EPSSMs) through the analysis of known HLA ligands and achieved relatively accurate prediction of detrimental and tolerated amino acid substitutions. Initial analysis of amino acid substitutions in CTL epitopes with degenerate recognition showed strong position-specific preferences. This first systematic analysis further suggested that spatial constraint may be the major molecular factor determining the degenerate epitope recognition. As the data cumulates, we anticipate that eventually EPSSMs will be available for prediction of degenerate T-cell epitope recognition.