Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies

Abstract

Summary Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here we study the B cell response in a bnAb-producing individual, and report cooperation between two B cell lineages to drive bnAb development. We isolated an autologous virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization—traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both autologous and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals.

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

“…Rather, with increasing heterologous breadth of neutralization the CH103 lineage retained the ability to neutralize evolving autologous viruses (Figure 2). This observation gave rise to the discovery of another antibody lineage in the CH505 individual that selected Env variants that were resistant to it, but sensitive to CH103, a phenomenon we termed B cell lineage cooperation (see below) (18). The evolution of the CH103 lineage antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope (17) and viral evolution of the loop D, a binding site for the CH103 lineage, was of particular interest.…”

“…The evolution of the CH103 lineage antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope (17) and viral evolution of the loop D, a binding site for the CH103 lineage, was of particular interest. The loop D was under intense pressure from the very early phases of acute infection: first amino acid substitutions arose as early as 4 weeks post-transmission and by 53 weeks post-transmission no virus was isolated that retained the TF virus amino acid sequence (18). …”

“…In African individual CH505, all viruses with mutated motifs in loop D were more sensitive to CH103 lineage antibody neutralization than the TF virus, implying that those mutations, despite being part of the binding site of the CH103 bnAb lineage, were selected by antibodies distinct from those in the CH103 B cell lineage (18). We identified the CH235 autologous neutralizing B cell lineage that cooperated with the CH103 lineage by selecting escape mutants with loop D mutations that made the virus more sensitive to CH103 (18).…”

“…Rather, analysis of the autologous virus quasispecies neutralization suggested that the PCDN lineage was triggered by a virus variant that emerged in-between 5 and 10 months post-transmission after removal of the N-linked glycosylation site at position 335 and a E328K mutation (20), suggesting the early presence of cooperating lineages (18). …”

“…First, the TF can engage the B cell receptor of a naïve, unmutated B cell and initiate B cell proliferation and accumulation of somatic mutations in V(D)J rearrangements as shown in Figure 3: for example, CD4bs bnAbs CH103 (17) and CH235 (18) derived from an African clade C HIV-1-infected individual bound to the autologous TF Env. Second, the TF Env may not engage the HIV-1 antibody UCA but rather engages latter members of the antibody lineage (Figure 6).…”