Emergence of Broadly Neutralizing Antibodies and Viral Coevolution in Two Subjects during the Early Stages of Infection with Human Immunodeficiency Virus Type 1

Abstract

Delineating the key early events that lead to the development of broadly neutralizing anti-HIV-1 antibodies during natural infection may help guide the development of immunogens and vaccine regimens to prevent HIV-1 infection. In this study, we monitored two HIV-1-positive subjects, VC20013 and VC10014, over the course of infection from before they developed broadly neutralizing antibody (bNAb) activity until several years after neutralizing breadth was detected in plasma. Both subjects developed bNAb activity after approximately 1 year postinfection, which ultimately mapped to the membrane-proximal external region (MPER) in VC20013 and an epitope that overlaps the CD4 receptor binding site in VC10014. In subject VC20013, we were able to identify anti-MPER activity in the earliest plasma sample that exhibited no bNAb activity, indicating that this epitope specificity was acquired very early on, but that it was initially not able to mediate neutralization. Escape mutations within the bNAb epitopes did not arise in the circulating envelopes until bNAb activity was detectable in plasma, indicating that this early response was not sufficient to drive viral escape. As bNAb activity began to emerge in both subjects, we observed a simultaneous increase in autologous antienvelope antibody binding affinity, indicating that antibody maturation was occurring as breadth was developing. Our findings illustrate one potential mechanism by which bNAbs develop during natural infection in which an epitope target is acquired very early on during the course of infection but require time and maturation to develop into broadly neutralizing activity. IMPORTANCEOne major goal of HIV-1 vaccine research is the development of a vaccine that can elicit broadly neutralizing antibodies (bNAbs). Although no such vaccine exists, bNAbs develop in approximately 20% of HIV-1-infected subjects, providing a prototype of the bNAbs that must be reelicited by vaccine. Thus, there is significant interest in understanding the mechanisms by which bNAbs develop during the course of infection. We studied the timing, epitope specificity, and evolution of the bNAb responses in two HIV-1-positive patients who developed bNAb activity within the first several years after infection. In one subject, antibodies to a broadly neutralizing epitope developed very early but were nonneutralizing. After several months, neutralizing activity developed, and the virus mutated to escape their activity. Our study highlights one mechanism for the development of bNAbs where early epitope acquisition followed by sufficient time for antibody maturation drives the epitope-specific antibody response toward broadly neutralizing activity.

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…Using BLI, surface plasmon resonance, and ELISA, we previously showed that the soluble trimeric Env proteins used in this study as vaccines bind strongly to several potent bNmAbs that target conformational epitopes on the HIV-1 trimeric Env spike (22). The binding experiments also correlated well with neutralization of pseudoviruses expressing immunogens envs by neutralizing mAbs (NmAbs) (27). The gp140 Env trimer immunogens in these studies possess some but not all of the structural and antigenic components of native infectious virions.…”

“…We have previously mapped bNAb activity of the human subject VC10014 to gp120 and the bNAb activity associated with VC20013 to the MPER of gp41 (27). Autologous anti-MPER NAbs were present during early infection (,1 y) and before heterologous neutralizing Abs (HNAbs) appeared in VC20013 (27).…”

“…Binding kinetics between polyclonal human IgG and HIV-1 SF162 gp140 trimers and Env immunogen trimeric proteins were also assessed with BLI as described previously (27).…”

“…However, the NAbs in the rabbits neutralized only Tier 1 viruses moderately with negligible evidence of ANabs. On the basis of our characterization of envs from VC10014 and VC20013 (27), the vaccine env clones exhibited a Tier 2 neutralization phenotype. Importantly, achieving Tier 2 neutralization represents a substantial advance in generating an effective humoral response.…”

“…Breadth in subject VC10014 was attributed to an epitope in gp120 that overlaps the CD4 binding site (CD4bs), and VC10013 breadth was mapped to a previously unrecognized epitope in the membrane proximal external region (MPER) of gp41. In these subjects, only a few critical epitopes that emerged within the first 2 y of infection accounted for affinity maturation resulting in distinctly unique pathways, leading to moderate breadth (27). After cloning and assessing a sizeable collection of gp160 env quasispecies representing the longitudinal evolution of env circulating within each individual, we designed DNA and protein vaccines using native envs and systematically conducted multiple comparative immunogenicity studies in rabbits (22).…”