Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection

Abstract

Purpose of Review Detailed genetic and structural characterization has revealed that broadly neutralizing antibodies (bnAbs) against HIV-1 have unusually high levels of somatic hypermutation, long CDRH3 domains, and the ability to target one of four sites of vulnerability on the HIV-1 envelope (Env) glycoproteins. A current priority is to understand how bnAbs are generated during natural infection, and translate this information into immunogens that can elicit bnAb following vaccination. Recent Findings Strain-specific neutralizing antibodies (nAb) can acquire broad neutralizing capacity when the transmitted/founder Env or a specific Env variant is recognized by an unmutated rearranged germline that has the capacity to develop bnAb like features. This could be a relatively infrequent event, as only certain germlines appear to possess inherent features needed for bnAb activity. Furthermore, the glycosylation pattern and diversity of circulating HIV-1 Envs, as well as the state of the B cell compartment, may influence the activation and maturation of certain antibody lineages. Summary Collectively, studies over the last year suggest that the development of HIV-1 Env immunogens that bind and activate bnAb-like germlines is feasible. However, more information about the features of Env variants and the host factors that lead to breadth during natural infection is needed to elicit bnAbs through immunization.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…The development of antibody responses follows a pattern, with antiviral antibodies being detected first as immune complexes41 followed by free antibody directed at the HIV‐1 envelope (Env) glycoprotein 41 (gp41) subunit,41, 42 and then by the development of Env glycoprotein 120 (gp120)‐binding antibodies 41. These early antibody responses do not neutralize or place selective pressure on virus evolution41; antibodies capable of neutralizing autologous viruses are not detectable until weeks to months after infection is established19, 20 and have little to no activity against heterologous HIV‐1 strains 43. The initial gp41‐directed antibody response is polyreactive and the antibodies are highly mutated,42 and evidence indicates that at least some early responding B cells are primed prior to infection by non‐HIV‐1 antigens such as proteins contained in intestinal microbiota 44…”

“…Acutely HIV‐1‐infected individuals do not make bnAbs,41, 43 but during chronic HIV‐1 infection, neutralization breadth develops to a greater or lesser degree in each person 45, 46, 47. Breadth of plasma neutralizing activity develops incrementally,48 and evidence suggests that protracted exposure to HIV‐1 Env is required 22, 23, 24, 47, 48, 49, 50.…”

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

“…The ontogenic pathways for each of these classes are distinct 25. Ongoing work aims to use the Antibodyomics2 technology to elucidate the pathways taken by broadly neutralizing antibodies targeting other sites of viral vulnerability.…”

Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency

“…5) and how bnmAbs evolve over the course of infection (reviewed in refs. 6,7). In this issue, Willis and collaborators further extend this knowledge through their employment of a computer model to predict mutations that markedly improved the neutralization potency and breadth of PG9 (8).…”