Tracing HIV-1 strains that imprint broadly neutralizing antibody responses. Nature
Kouyos et al. aimed to identify the viral determinants of a broadly neutralizing immune response in HIV-infected humans. The study-hypothesis was that if viral factors determine the quality of the antibody response, individuals with closely related viral strains would have similar neutralization responses.
The authors identified 303 transmission pairs from the SHCS based on the sequence similarity of their HIV-1 polymerase gene. They then tested the ability of the antibody response in these individuals to neutralize 14 different virus strains and to bind 13 antigens (‘antibody fingerprint’).
They found that transmission pairs had a more similar antibody fingerprint than pairs that were randomly assigned. Specifically, the infecting virus determined 13.2% in the variability of neutralization responses and 7–19% of the IgG reactivity. When taking into account factors that are known to influence broadly neutralizing antibody (bnAb) development, such as duration of infection and HIV-1 subtype, the correlation between infecting virus and the neutralization fingerprint remained in a similar range. Although the association between virus genetics and neutralization was highly statistically significant, the average effect size was moderate, similar to the effect size of virus genetics on CD4+ T cell loss. Remarkably, the authors found one transmission pair of elite neutralizers: this pair had developed a broadly neutralizing response by testing 42 different HIV-1 strains; that is, the pair had neutralization levels in the top 1% of the original cohort in which the transmission pairs were identified. The authors determined that the probability of finding a pair with such a strong and similar bnAb response by chance is low at 0.017.
In summary, the study shows that differences in HIV-1 genetics influence the development of antibody responses and that some viral variants can elicit bnAbs across individuals. Although such strong bnAb imprinting is likely to be rare, the viral strains and antigens that underlie this effect are prime candidates for vaccine development.