HIV-1 neutralizing antibodies: understanding nature's pathways

Abstract

The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus-1 (HIV-1) and its ability to escape a myriad of host immune responses. In addition, conserved vulnerable regions on the HIV-1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV-1-infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV-1-infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination.

Fig. 1. Coevolution of virus and a single antibody lineage in an HIV-1 seroconverter

Mature CD4-binding site antibodies CH103-106 were isolated from circulating memory B-cells at week 136. Longitudinal sampling allowed inference and reconstruction of the evolution of the infecting viral sequence and of the specific neutralizing antibody lineage. The heavy chain antibody lineage was augmented with sequences derived from B-cell gene sequencing and bioinformatics analyses were used to infer early intermediates (IA) and the unmutated ancestor (UA). The left part of the figure displays a phylogenetic tree of Env sequences derived from week 4 through week 160. The UA and IA heavy chain sequences of the CH103 antibody lineages are shown alongside viral evolution. This antibody lineage evolved to gain high affinity Env binding, and virus neutralization evolved from strain-specific autologous virus activity to cross-reactive neutralization of heterologous viruses.

Fig. 2. B-cell lineage-based approach to vaccine design

Mature BNAbs can be isolated from HIV-1 infected donors using modern methods such as memory B-cell culture or sorting of antigen-specific B-cells. Based on the known BNAb sequence, next generation sequencing can be used to find numerous clonal relatives of the mature BNAb. If appropriate longitudinal samples are available, it is possible to infer the full antibody lineage, including the UA and IA. The expressed UA and IA sequences can then be used as templates for the design of HIV-1 immunogens with high affinity binding. Since the antibody lineage is known to evolve in response to viral evolution, it may be possible to design sequential immunogens with high affinity binding for the UA and IA, thus guiding the antibody response toward the mature antibody with broad neutralizing activity.