Isolation and characterization of HIV-1 neutralizing antibodies from infants

Abstract

Developing a protective HIV vaccine remains a key goal of prevention efforts. Broadly neutralizing antibodies (bnAbs) that recognize diverse circulating strains of HIV are thought to be an important component of a protective vaccine but eliciting such responses remains elusive. bnAbs that have been isolated from HIV-infected adults exhibit several unusual features that present obstacles to their elicitation such as the requirement for high levels of somatic hypermutation (SHM) and long-term antibody maturation for broad activity. Efforts are ongoing to characterize the development of bnAbs following infection to guide immunogen design and vaccine strategies to elicit them despite these immunological barriers. HIV-infected infants develop bnAbs with more rapid kinetics than adults, suggesting that infant responses could inform a more straightforward path to achievable vaccine targets. To understand these unique pediatric responses, we isolated and characterized infant HIV-neutralizing antibodies (nAbs) and defined the development of an infant-derived bnAb. First, we isolated nAbs contributing to a broad plasma response at one year post-infection from infant BF520. We observed that polyclonal nAbs with low SHM contribute to plasma neutralizing activity. Additionally, we isolated one infant-derived bnAb that targets a known conserved site of vulnerability on HIV envelope (Env) commonly targeted by adult bnAbs. This infant bnAb is distinct from adult bnAbs in that it utilizes different germline genes, has very low SHM, and importantly, lacks rare insertions and deletions that have been shown to be critical for the activity of most adult antibodies targeting this epitope. The identification of this infant bnAb illustrates that HIV-1-specific neutralization breadth can develop without prolonged affinity maturation and extensive SHM. Next, we characterized the ontogeny of the infant-derived bnAb by reconstructing the naïve progenitor and developmental intermediates. We observed that the naïve antibody recognizes HIV Env, which contrasts with precursors of many adult bnAbs. The ability to neutralize viruses from multiple clades developed within six months of infection and the full breadth of the mature antibody was reached with as little as 3% SHM. Remarkably, substitutions in the kappa chain enabled both autologous and heterologous neutralization. This study provides a template for the design of vaccine strategies to elicit similar responses by identifying Env isolates that could be used as sequential immunogens. Finally, we isolated and characterized nAbs contributing to plasma breadth at two years post-infection from infant BG505. This infant is of particular interest to the HIV field because the Env of the transmitted virus from BG505 has been extensively characterized in numerous structural and vaccine studies, and understanding the nAbs that developed following infection with this Env complements those studies. We isolated polyclonal nAbs from multiple expanded clonal families contributing to heterologous neutralizing activity. These studies showed that infant antibodies have features distinct from adult antibodies, including several that may be amenable to better vaccine responses. This work represents the first isolation and characterization of a HIV-bnAb from an infant and highlights the potential of the infant immune system to develop polyclonal nAbs against HIV. Future studies should focus on characterizing nAbs contributing to broad plasma responses in additional infants to inform how to elicit bnAbs by vaccination.