Only few people that are infected with HIV-1 develop broadly neutralizing antibodies (bnAbs), which target conserved viral antigens and thus can neutralize diverse viral variants. The factors that determine whether someone will develop bnAbs are not entirely clear; in particular, the contribution of virus characteristics is unknown. Identifying viral determinants of a broadly neutralizing immune response would be very helpful for vaccine development. Kouyos et al. investigated the antibody responses in a large cohort of HIV-1 transmission pairs within the Swiss HIV Cohort Study and found that the HIV-1 strain that someone is infected with determines part of the breadth and strength of the antibody response.

The authors hypothesized that if viral factors determine the quality of the antibody response, individuals with closely related viral strains would have similar neutralization responses. To test this hypothesis, they identified 303 transmission pairs 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, determining what the authors call the ‘antibody fingerprint’ of the infecting virus. Indeed, 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 (depending on the IgG class), which confirms that the infecting virus can imprint the neutralization capacity of the ensuing antibody response. Even when taking into account factors that are known to influence 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.

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Although this 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. HIV-1 is a hugely variable virus and some viral variants might be much stronger ‘imprinters’. Remarkably, the authors found one transmission pair of so-called elite neutralizers; that is, the pair had neutralization levels in the top 1% of the original cohort in which the transmission pairs were identified. The authors confirmed that this pair had developed a broadly neutralizing response by testing 42 different HIV-1 strains and they determined that the probability of finding a pair with such a strong and similar bnAb response by chance is low at 0.017.

the HIV-1 strain that someone is infected with determines part of the breadth and strength of the antibody response

In summary, Kouyos et al. found 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.