|Yacoob, Christina - Fred Hutchinson Cancer Research Center|
|Cohen, Kristen - Fred Hutchinson Cancer Research Center|
|Lathia, Kanan - Fred Hutchinson Cancer Research Center|
|Feng, Junli - Fred Hutchinson Cancer Research Center|
|Glenn, Jolene - Fred Hutchinson Cancer Research Center|
|Carbonetti, Sara - Center For Infectious Disease Research|
|Oliver, Brian - Center For Infectious Disease Research|
|Vigdorovich, Vladimir - Center For Infectious Disease Research|
|Sather, D. Noah - Center For Infectious Disease Research|
|Stamatatos, Leonidas - Fred Hutchinson Cancer Research Center|
Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/24/2018
Publication Date: 6/22/2018
Citation: Yacoob, C., Lange, M.D., Cohen, K., Lathia, K., Feng, J., Glenn, J., Carbonetti, S., Oliver, B., Vigdorovich, V., Sather, D., Stamatatos, L. 2018. B cell clonal lineage alterations upon recombinant HIV-1 envelope immunization of Rhesus macaques. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1007120.
DOI: https://doi.org/10.1371/journal.ppat.1007120 Interpretive Summary: Broadly neutralizing antibodies isolated from HIV-1 infected subjects display protective potential in animal models. The HIV-1 envelope glycoprotein (Env) is the sole viral target of broad neutralizing antibodies, but is also targeted by binding, non-neutralizing antibodies. The use of different components of the HIV-1 envelope to produce broadly neutralizing antibodies has mostly generated polyreactive antibodies to specific immunogenic determinants. It is currently not known why the development of broad neutralizing antibodies is so inefficient against HIV-1. A non-human primate model system was used to test and characterize the humoral immune response to different HIV-1 immunogens. The rhesus macaque adaptive immune response was evaluated through the serological and sequence analyses of distinct B cell responses among differing tissue sites in multiple animals. The clade C HIV Env 426c constructs: (1) the full length extracellular portion of Env and (2) extracellular portion of Env lacking the variable domains 1, 2 and 3 and three conserved N-linked glycosylation sites both generated antibodies, however only one the truncated construct developed broad neutralizing antibodies to a very restricted B cell repertoire. These results demonstrate the differences between immunogens and their ability to activate different B cell populations.
Technical Abstract: 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.