Abstract
A likely key factor in the failure of a HIV-1 vaccine based on cytotoxic T lymphocytes (CTL) is the natural immunodominance of epitopes that fall in variable regions of the proteome, which both increases the chance of epitope sequence mismatch with the incoming challenge strain and replicates the pathogenesis of early CTL failure due to epitope escape mutation during natural infection. To identify potential vaccine sequences to focus the CTL response on highly conserved epitopes, the whole proteomes of HIV-1 clades A1, B, C, and D were assessed for Shannon entropy at each amino acid position. Highly conserved regions in Gag (cGag-1, Gag 148–214, and cGag-2, Gag 253–331), Env (cEnv, Env 521–606), and Nef (cNef, Nef 106–148) were identified across clades. Inter- and intra-clade variability of amino acids within the regions tended to overlap, suggesting that polyvalent representation of consensus sequences for the four clades would allow broad HIV-1 strain representation. These four conserved regions were rich in both known and predicted CTL epitopes presented by a breadth of HLA types, and screening of 54 persons with chronic HIV-1 infection revealed that these regions are commonly immunogenic in the context of natural infection. These data suggest that vaccine delivery of a 16-valent mixture of these regions could focus the CTL response against conserved epitopes that are broadly representative of circulating HIV-1 strains.
Highlights
Efforts to design a vaccine against Human Immunodeficiency Virus type 1 (HIV-1) have been disappointing
To assess sequence variability and conservation across the viral proteome, all available clade B complete HIV-1 protein sequences in the Los Alamos National Laboratory (LANL) HIV Sequence Database were assessed for Shannon entropy at each amino acid position
Each region contained many previously reported cytotoxic T lymphocyte (CTL) epitopes associated with a variety of HLA types, as well as binding motifs for many additional HLA types. These findings suggested that these conserved regions contain many epitopes that can be presented by a broad range of HLA types, and should be immunogenic for CTL responses from most persons
Summary
Efforts to design a vaccine against Human Immunodeficiency Virus type 1 (HIV-1) have been disappointing. The first unsuccessful attempts included strategies using inactivated whole virus or virus protein subunits, which would be expected to raise antibodies and HLA class II-restricted helper responses against HIV-1. When such approaches (including a phase III trial of the HIV-1 envelope-based ‘‘AIDSVAX’’) failed to produce protective humoral immunity, researchers turned to the idea that a vaccine to elicit HLA class I-restricted cytotoxic T lymphocyte (CTL) responses might provide protection against disease if not infection, given the increasingly clearly protective role of CTL in the immunopathogenesis of HIV-1 infection. The attempts to generate HIV-1-specific CTL responses with a vaccine have focused heavily upon vector development for immunogenicity, as safety concerns precluded the classical empiric approach of using live-attenuated HIV-1. The first large efficacy trial of this approach was halted for futility at mid-enrollment, when interim safety analysis revealed that there was no difference in infection incidence or set-point viremia levels after infection between placebo and vaccine arms [2]
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