Abstract
The specificity and intensity of CD4(+) helper T-cell responses determine the effectiveness of immune effector functions. Promiscuously immunodominant helper T-cell epitopes in the human immunodeficiency virus (HIV) envelope glycoprotein gp120 could be important in the development of broadly protective immunity, but the underlying mechanisms of immunodominance and promiscuity remain poorly defined. In this study, gp120 helper T-cell epitopes were systematically mapped in CBA/J and BALB/c mice by restimulation assays using a set of overlapping peptides spanning the entire sequence of the gp120 encoded by HIV strain 89.6. The results were analyzed in the context of the HIV gp120 structure determined by x-ray crystallography. One major finding was that all of the promiscuously immunodominant gp120 sequences are located in the outer domain. Further analyses indicated that epitope immunogenicity in the outer domain correlates with structural disorder in adjacent N-terminal segments, as indicated by crystallographic B-factors or sequence divergence. In contrast, the correlation was poor when the analysis encompassed the entire gp120 sequence or was restricted to only the inner domain. These findings suggest that local disorder promotes the processing and presentation of adjacent epitopes in the outer domain of gp120 and therefore reveal how three-dimensional structure shapes the profile of helper T-cell epitope immunogenicity.
Highlights
The human immunodeficiency virus (HIV)/AIDS1 epidemic continues to be a serious health threat worldwide
Immunodominant helper T-cell epitopes in the human immunodeficiency virus (HIV) envelope glycoprotein gp120 could be important in the development of broadly protective immunity, but the underlying mechanisms of immunodominance and promiscuity remain poorly defined
Gp120 helper T-cell epitopes were systematically mapped in CBA/J and BALB/c mice by restimulation assays using a set of overlapping peptides spanning the entire sequence of the gp120 encoded by HIV strain 89.6
Summary
KEKTWVTIYYGVPVWREATT GVPVWREATTTLFCASDAKA TLFCASDAKAYDTEVHNVWA YDTEVHNVWATHACVPTDPN THACVPTDPNPQEVVLGNVT PQEVVLGNVTENFNMWKNNM ENFNMWKNNMVDQMHEDIIS VDQMHEDIISLWDESLKPCV LWDESLKPCVKLTPLCVTLN KLTPLCVTLNCTNLNITKNT CTNLNITKNTTNPTSSSWGM TNPTSSSWGMMEKGEIKNCS MEKGEIKNCSFYITTSIRNK FYITTSIRNKVKKEYALFNR VKKEYALFNRLDVVPIENTN LDVVPIENTNNTKYRLISCN NTKYRLISCNTSVITQACPK TSVITQACPKVSFQPIPIHY VSFQPIPIHYCVPAGFAMLK CVPAGFAMLKCNNKTFNGSG CNNKTFNGSGPCTNVSTVQ PCTNVSTVQCTHGIRPVVST THGIRPVVSTQLLLNGSLAE QLLLNGSLAEEDIVIRSENF EDIVIRSENFTDNAKTIIVQ TDNAKTIIVQLNESVVINCT LNESVVINCTRPNNNTRRRL RPNNNTRRRLSIGPGRAFYA SIGPGRAFYARRNIIGDIRQ RRNIIGDIRQAHCNISRAKW AHCNISRAKWNNTLQQIVIK NNTLQQIVIKLREKFRNKTI LREKFRNKTIAFNQSSGGD AFNQSSGGDPEIVMHSFNCG EIVMHSFNCGGEFFYCNTAQ GEFFYCNTAQLFNSTWNVTG LFNSTWNVTGGTNGTEGNDI GTNGTEGNDIITLQCRIKQI ITLQCRIKQIINMWQKVGKA INMWQKVGKAMYAPPITGQI MYAPPITGQIRCSSNITGLL RCSSNITGLLLTRDGGNSTE LTRDGGNSTETETEIFRPGG TETEIFRPGGGDMRDNWRSE GDMRDNWRSELYKYKVVRIE LYKYKVVRIEPIGVAPTRAK PIGVAPTRAKRRTVQREKR epitope immunodominance at the level of tertiary structure in the antigen. One recent study systematically characterized the specificity of T-cell clones derived from immunized C57BL/6 mice and interpreted the results in light of the crystal structure of gp120 [39] These authors noted the frequent occurrence of helper T-cell epitopes near exposed strands of gp120 and concluded that the pattern could be related to antigen processing. This conclusion is consistent with our previous work suggesting that structurally disordered regions within protein antigens direct presentation of adjacent sequences by providing preferred sites of proteolytic cleavage [40, 41]. The resulting gp120 helper T-cell epitope patterns were correlated with domain structure and segmental disorder in gp120
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
