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B cell clonal lineage alterations upon recombinant HIV-1 envelope immunization of rhesus macaques

by Christina Yacoob, Miles Darnell Lange, Kristen Cohen, Kanan Lathia, Junli Feng, Jolene Glenn, Sara Carbonetti, Brian Oliver, Vladimir Vigdorovich, David Noah Sather, Leonidas Stamatatos

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.

Authors:   Christina Yacoob; Miles Darnell Lange; Kristen Cohen; Kanan Lathia; Junli Feng; Jolene Glenn; Sara Carbonetti; Brian Oliver; Vladimir Vigdorovich; David Noah Sather; Leonidas Stamatatos
Journal:   PLoS Pathogens
Volume:   14
edition:   6
Year:   2018
Pages:   e1007120
DOI:   10.1371/journal.ppat.1007120
Publication date:   22-Jun-2018
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