Abstract
Background: Current HIV-1 envelope glycoprotein (Env) vaccines are unable to induce cross-reactive neutralizing antibodies. However, such antibodies are elicited in 10-30% of HIV-1 infected individuals, but it is unknown why these antibodies are induced in some individuals and not in others. We hypothesized that the Envs of early HIV-1 variants in individuals who develop cross-reactive neutralizing activity (CrNA) might have unique characteristics that support the induction of CrNA. Results: We retrospectively generated and analyzed env sequences of early HIV-1 clonal variants from 31 individuals with diverse levels of CrNA 2-4 years post-seroconversion. These sequences revealed a number of Env signatures that coincided with CrNA development. These included a statistically shorter variable region 1 and a lower probability of glycosylation as implied by a high ratio of NXS versus NXT glycosylation motifs. Furthermore, lower probability of glycosylation at position 332, which is involved in the epitopes of many broadly reactive neutralizing antibodies, was associated with the induction of CrNA. Finally, Sequence Harmony identified a number of amino acid changes associated with the development of CrNA. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region as well as the underlying α2 helix of the third constant region. Conclusions: These findings imply that the development of CrNA might depend on specific characteristics of early Env. Env signatures that correlate with the induction of CrNA might be relevant for the design of effective HIV-1 vaccines.