Limited breadth of a T-helper cell response to a human immunodeficiency virus envelope protein

Abstract

Single-envelope human immunodeficiency virus (HIV) vaccines have been studied for more than a decade, with some successes in homologous challenge experiments in nonhuman primates but with no clear successes in clinical trials. To gain insight into the breadth of the immunity elicited by such vaccines, we have dissected the T-helper cell response of C57BL/6 mice to an individual, molecularly cloned envelope protein. Here, we report that T-helper cells responsive to HIV type 1 1035 envelope are very highly restricted in C57BL/6 animals: seven different hybridomas recovered from five separate mice recognized the same peptide, PKVSFEPIPIHYCAP, located in the C2 region of gp120. Three of these hybridomas were tested on a natural variant of the peptide but failed to respond. A more extensive analysis of whole splenic populations from other C57BL/6 mice immunized with the 1035 envelope reproducibly confirmed that the gp120-specific T-helper response was almost exclusively focused on a single epitope. We conclude that single-envelope vaccines may frequently fail to provoke an immune response sufficiently diverse to recognize variant sequences among circulating HIV. The results encourage the inclusion of more than one envelope in future vaccines to enhance the potential diversity and respective surveillance capacities of responding T-helper cell populations.

FIG. 1.

HIV 1035 gp120 envelope sequence. The 1035 gp120 envelope sequence is shown, and sequences represented by each of 20 peptide pools are indicated; 8- to 15-mer peptides spanned the envelope sequence with overlaps of ∼10 amino acids.

FIG. 2.

T-helper cells from C56BL/6 mice respond predominantly to a single peptide in the HIV 1035 gp120 sequence. (A) Spleen cells from eight 1035 envelope-primed mice were pooled and measured by ELISPOT assay against 20 peptide pools spanning the gp120 sequence. Each pool contained five sequential peptides (8- to15-mers). The blue spots represent IFN-γ-producing, peptide-specific cells from immunized spleens. A concanavalin A control is also shown. (B) Results with negative control cells from a naive spleen are shown.