HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant

Abstract

SUMMARY HIV-1 broadly neutralizing antibodies (bnAbs) develop in a subset of infected adults and exhibit high levels of somatic hypermutation (SHM) due to years of affinity maturation. There is no precedent for eliciting highly mutated antibodies by vaccination, nor is it practical to wait years for a desired response. Infants develop broad responses early, which may suggest a more direct path to generating bnAbs. Here, we isolated ten neutralizing antibodies (nAbs) contributing to plasma breadth of an infant at ~1 year post-infection, including one with cross-clade breadth. The nAbs bind to envelope trimer from the transmitted virus suggesting this interaction may have initiated development of the infant nAbs. The infant cross-clade bnAb targets the N332 supersite on envelope, but unlike adult bnAbs targeting this site, lacks indels and has low SHM. The identification of this infant bnAb illustrates that HIV-1-specific neutralization breadth can develop without prolonged affinity maturation and extensive SHM.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…While the V3-glycan epitope centers on the glycan at N332, high-mannose glycans at other positions can variably be involved in the bnAb epitope (46–49). Such diversity is reflected in crystal and electron microscopy structures by different angles of approaches of individual V3-glycan bnAbs (24, 28,45,46,48–50) (Wilson and Ward, this volume). The V3-glycan bnAb class is of interest for vaccine development because it does not require extensive somatic hypermutation to develop neutralization breadth.…”

“…The V3-glycan bnAb class is of interest for vaccine development because it does not require extensive somatic hypermutation to develop neutralization breadth. Indeed, V3-glycan neutralizing antibodies with limited levels of somatic mutation but neutralization breadth have been recently described in an adult (20), and as well, in an infant within 1 year from infection (28). Finally, the composition of the core epitope (4 amino acids and a high mannose glycan at position N332) has facilitated the synthesis of a minimal bnAb epitope construct (Alam S.M.…”

“…The development of V3-glycan bnAb B cell lineages over time and the co-evolution with autologous TF virus have been recently elucidated by three independent groups in different individuals: chronically HIV-1 infected adult individuals PC76 (20) and CH848 (Bonsignori M. et al, submitted), and an infant who became infected during the first 4 months after birth, likely through breastfeeding (28). …”

“…From an infant who became infected with a clade A virus within 3.8 months of age and acquired plasma Tier 2 neutralizing activity by 1 year of age (29), Simonich and colleagues isolated 8 non-clonally related heterologous Tier 2-neutralizing antibodies from memory B cells collected at 15 months of age (11.2 months post-infection) (28). All infant neutralizing antibodies displayed low levels of somatic mutations (2.0 – 6.6%).…”

“…In HIV-1 infected adults, plasma levels of bnAbs usually develop after 2–4 years of infection. However, in children, examples of plasma bnAb breath occurring within the first year of HIV-1 infection have been reported (28, 29). Because many bnAbs have unusual traits of high levels of somatic mutations, long third heavy chain complementarity regions (CDR H3s) and/or poly- or auto-reactivity, it has been postulated that bnAb maturation is disfavored due to control by host tolerance mechanisms (31, 32) (Kelsoe and Haynes, this volume; Verkoczy, Tian and Alt, this volume).…”