Improving on nature: Focusing the immune response on the V3 loop

The conventional wisdom suggests that "constant" rather than "variable" regions of the HIV envelope (Env) glycoproteins would induce the most broadly reactive antibodies (Abs). However, of the several epitopes in the conserved regions of gp120 and gp41 that induce neutralizing Abs, all are well-protected by protein folding, glycosylation, and/or oligomerization of the Env proteins on the virus surface; most are only transiently exposed during the process of infection or are poorly immunogenic. In contrast, the third variable region (V3) of gp120 appears to be at least partially exposed during various stages of the infectious process, is immunogenic in essentially all HIV+ subjects, and is capable of inducing Abs able to neutralize a broad array of primary isolates. While these Abs were originally thought to be isolate-specific, a large body of data now shows that anti-V3 Abs from HIV-infected individuals indeed show intra- and inter-clade cross-reactivity with respect to both binding to diverse gp120 molecules and neutralization of many primary isolates. This cross-reactivity of anti-V3 Abs is counter-intuitive if one focuses on the sequence variability rather than on the conserved V3 structures which must be present in order to allow this region of the virus envelope to mediate selection of and interaction with chemokine receptors. Current data, summarized here, support the hypothesis that the V3 region of gp120 can induce broadly-reactive, cross-neutralizing Abs and as such should constitute a prominent target of the immune response induced with an HIV vaccine.