Allocation of helper T-cell epitope immunodominance according to three-dimensional structure in the human immunodeficiency virus type I envelope glycoprotein gp120

The specificity and intensity of CD4(+) helper T-cell responses determine t he 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 protect ive immunity, but the underlying mechanisms of immunodominance and promiscu ity remain poorly defined. In this study, gp120 helper T-cell epitopes were systematically mapped in CBA/J and BALB/c mice by restimulation assays usi ng 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 locat ed in the outer domain. Further analyses indicated that epitope immunogenic ity in the outer domain correlates with structural disorder in adjacent N-t erminal segments, as indicated by crystallographic D-factors or sequence di vergence. In contrast, the correlation was poor when the analysis encompass ed the entire gp120 sequence or was restricted to only the inner domain. Th ese findings suggest that local disorder promotes the processing and presen tation of adjacent epitopes in the outer domain of gp120 and therefore reve al how three-dimensional structure shapes the profile of helper T-cell epit ope immunogenicity.