Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model
Musharrafieh, R.; Safonova, Y.; Song, G.; Roark, R. S.; Lee, F.-H.; Zhang, S.; Hurtado, J.; Yong, P.; Wang, S.; Russell, R. M.; Ding, W.; Li, Y.; Rando, J.; Murphy, A. I.; Lindemuth, E.; Zhao, C.; Connell, A. J.; Lee, W.-H.; Mishra, N.; Avillion, G.; He, W.; Callaghan, S.; Dueker, K.; Vo, A. L.; Li, X.; Capozzola, T.; Joyce, C.; Zhao, F.; Anzanello, F.; Liu, W.; Bibollet-Ruche, F.; Ramos, A.; Li, H.; Lewis, M. G.; Ozorowski, G.; Landais, E.; Foley, B. T.; Wagh, K.; Sok, D.; Briney, B.; Ward, A. B.; Hahn, B. H.; Burton, D. R.; Shaw, G. M.; Andrabi, R.
10.1101/2023.09.21.558743 bioRxivShow abstract
Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/558743v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@17673c8org.highwire.dtl.DTLVardef@1ab61a8org.highwire.dtl.DTLVardef@98781forg.highwire.dtl.DTLVardef@1f63e9b_HPS_FORMAT_FIGEXP M_FIG C_FIG
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