Rare twin cysteine residues in HIV-1 Env and neutralization breadth
This week we highlight the study by Hesselman et al., published in Cell Host & Microbe and awarded the SSI Award in Basic Research, titled “Rare twin cysteine residues in HIV-1 Env and neutralization breadth.”
Broadly neutralizing antibodies (bnAbs) against HIV-1 typically target the viral envelope (Env), with the variable V1V2 loops at the Env apex being key modulators of antibody sensitivity. Hesselman and colleagues analyzed more than 65,000 HIV-1 Env V1 sequences from multiple cohorts (Swiss HIV Cohort, Zurich Primary Infection Study, CAPRISA, and AMP trials) to investigate unusual cysteine insertions in this region. They discovered that ~18% of Env variants from elite neutralizers carried additional “twin cysteine” residues (C2 motif) in V1. These insertions likely stabilize Env via disulfide bonding, conferring modest but broad resistance to bnAbs.
Although rare (<10% prevalence in the general population), C2 variants were enriched among bnAb inducers, linking them to the development of antibody breadth. Longitudinal analyses showed that C2 variants can persist and even be transmitted without significant fitness costs, while also shifting epitope exposure: they reduce sensitivity to many bnAbs but increase accessibility to V2-apex–directed antibodies.
In summary, non-canonical cysteine motifs in the V1 loop represent a viral adaptation that promotes immune escape while facilitating the evolution of neutralization breadth. These findings suggest that incorporating V1 cysteine motifs into immunogen design may help guide bnAb development in future HIV vaccine strategies.