Date Published: June 22, 2018
Publisher: Public Library of Science
Author(s): Christina Yacoob, Miles Darnell Lange, Kristen Cohen, Kanan Lathia, Junli Feng, Jolene Glenn, Sara Carbonetti, Brian Oliver, Vladimir Vigdorovich, David Noah Sather, Leonidas Stamatatos, Guido Silvestri.
Broadly neutralizing HIV-1 antibodies (bNAbs) isolated from infected subjects display protective potential in animal models. Their elicitation by immunization is thus highly desirable. The HIV-1 envelope glycoprotein (Env) is the sole viral target of bnAbs, but is also targeted by binding, non-neutralizing antibodies. Env-based immunogens tested so far in various animal species and humans have elicited binding and autologous neutralizing antibodies but not bNAbs (with a few notable exceptions). The underlying reasons for this are not well understood despite intensive efforts to characterize the binding specificities of the elicited antibodies; mostly by employing serologic methodologies and monoclonal antibody isolation and characterization. These approaches provide limited information on the ontogenies and clonal B cell lineages that expand following Env-immunization. Thus, our current understanding on how the expansion of particular B cell lineages by Env may be linked to the development of non-neutralizing antibodies is limited. Here, in addition to serological analysis, we employed high-throughput BCR sequence analysis from the periphery, lymph nodes and bone marrow, as well as B cell- and antibody-isolation and characterization methods, to compare in great detail the B cell and antibody responses elicited in non-human primates by two forms of the clade C HIV Env 426c: one representing the full length extracellular portion of Env while the other lacking the variable domains 1, 2 and 3 and three conserved N-linked glycosylation sites. The two forms were equally immunogenic, but only the latter elicited neutralizing antibodies by stimulating a more restricted expansion of B cells to a narrower set of IGH/IGK/IGL-V genes that represented a small fraction (0.003–0.02%) of total B cells. Our study provides new information on how Env antigenic differences drastically affect the expansion of particular B cell lineages and supports immunogen-design efforts aiming at stimulating the expansion of cells expressing particular B cell receptors.
Following HIV-1 infection, serum neutralizing antibody responses against the evolving autologous viral swarm are generated by the vast majority of infected subjects, usually within the first few months of infection [1–6]. In 10–30% of infected subjects, antibodies capable of neutralizing not only the autologous virus but also heterologous viruses are generated, usually following several years of infection [2, 5, 7–13]. These neutralizing antibodies are referred to as broadly neutralizing antibodies (bNAbs). Binding but non-neutralizing antibodies (nNAbs) are also present in sera from infected subjects. Broadly neutralizing monoclonal antibodies isolated from HIV-1-infected subjects protect animals from experimental infection [14–23] and thus bNAbs are expected to be an important component of the protective immune response elicited by an effective HIV-1 vaccine. The viral envelope glycoprotein (Env) is the target for both nNAbs and bNAbs and the epitopes targeted by bNAbs and nNAbs have been identified and in many cases they have been structurally characterized [24–26]. In general, nNAbs target elements of Env that are variable in sequence and are located within the more exposed regions of Env on soluble gp120s or non-stabilized soluble gp140 proteins. In contrast, bNAbs bind conserved elements of Env.
Different concepts to elicit HIV-1 bNAbs through immunization are under investigation. One concept is based on the ‘germline-targeting’ approach during which a ‘germline-targeting’ immunogen is used to initiate the activation of naïve B cells expressing specific germline (unmutated) BCRs and subsequently, booster immunizations with specifically-designed immunogens to guide the maturation (through somatic hypermutation) of these BCRs towards their broadly neutralizing forms .