HIV-1 infections with multiple founders associate with the development of neutralization breadth

Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth. Author summaryVaccines against viral pathogens protect through the induction of broadly neutralizing antibodies (bnAbs). No HIV-1 vaccine has successfully elicited bnAbs, and a successful HIV-1 vaccine will need to accelerate the process of development of a broadly neutralizing response that typically takes a couple of years to develop in natural infection. We studied diversity in the HIV-1 envelope gene from initial infection to several years out in 126 individuals from two cohorts. We showed that the development of bnAbs at 2-3 years was not due to transmissible viral genetics, but rather associated with diversity during the first month of infection. We propose that designing a vaccine that mimics an infection with multiple, minimally distant founder variants may successfully elicit the development of bnAbs and provide effective prophylaxis against HIV-1.

Automated summary

This study investigates the relationship between diversity in the HIV-1 envelope gene and the development of neutralization breadth. The results suggest that the presence of slightly different HIV-1 variants in the early stages of infection may promote the induction of broadly neutralizing antibodies. Vaccination with a mixture of minimally distant antigens could be a potential strategy for eliciting broadly neutralizing antibodies.