The development and genetic origin of broadly neutralizing HIV antibodies

Abstract

Several of the most broadly neutralizing HIV antibodies (bnAbs) contain unique genetic or structural elements, including long heavy chain complementarity determining region 3 (HCDR3) loops and extensive somatic hypermutation. Two exceptionally broad, potently neutralizing HIV-specific antibodies, PG9 and PG16, encode HCDR3 loops that are among the longest of any antigen-specific antibody described to date. Passive immunization with two other bnAbs that encode long HCDR3s, 4E10 and 2F5, is able to protect against HIV infection. Induction of such long HCDR3 antibodies may be critical to the design of an effective vaccine strategy for HIV, however it is unclear at present how to induce such antibodies. There has been speculation that antibodies with long HCDR3s are generated primarily through the accumulation of somatic hypermutation-associated insertions. These short insertion events are rare, and design of an immunogen that efficiently induces many such insertions in a single antibody sequence is likely to be extremely difficult. Through the use of high-throughput antibody sequencing, I have identified genetic evidence that these long HCDR3 antibodies are typically formed at the original recombination event, not through accumulation of somatic hypermutation-induced insertions. Antibodies with long HCDR3s were found in all tested individuals, and long HCDR3 antibodies typically use a restricted subset of D and J gene segments, resulting in the incorporation of highly conserved genetic elements in the majority of such antibody sequences. This work provides an important first step toward the realization of a vaccine that efficiently induces broadly neutralizing HIV antibodies with long HCDR3s by identifying a conserved genetic target through which B cells encoding antibodies with long HCDR3s may be induced selectively through vaccination.