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Engineering HIV Immunogens to Elicit IOMA-like Antibodies Targeting the CD4 Binding Site

Gristick, Harry and van Schooten, Jelle and Hartweger, Harald and Abernathy, Morgan and Pavlovitch-Bedzyk, Jimena and Escolano, Amelia and West, Anthony and Nussenzweig, Michel and Bjorkman, Pamela (2018) Engineering HIV Immunogens to Elicit IOMA-like Antibodies Targeting the CD4 Binding Site. AIDS Research and Human Retroviruses, 34 (S1). p. 59. ISSN 0889-2229. doi:10.1089/aid.2018.5000.abstracts.

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Background: The most effective way to control the AIDS epidemic would be through active vaccination. The current focus of HIV vaccine design is induction of broadly neutralizing antibodies (bNAbs) against the HIV Envelope protein (Env) that neutralize the majority of circulating viral strains. Due to their breadth and potency, the most desirable bNAbs to elicit through immunization are the VRC01-class bNAbs that target the conserved host receptor (CD4) binding site (CD4bs). VRC01-class bNAbs mimic CD4 binding to share a common mode of gp120 binding and glycan accommodation using a VH1-2*02-derived variable heavy (VH) domain. While attractive candidates for immunogen design, features of VRC01-class bNAbs such as a high degree of somatic hypermutation (SHM) and a short (5-residue) light chain (LC) complementarity determining region 3 (CDRL3) (found in only 1% of human LCs) suggest they might be difficult to elicit through vaccination. We recently published a structural characterization of a novel VH1-2*02-derived CD4bs bNAb, named IOMA, that is an attractive target for immunogen design due to its relatively low levels of SHMs and normal-length CDRL3 (8 residues). Here we describe our work to design an immunogen that elicits IOMA-like antibodies by engineering a gp120 from the 426c Env. Methods: We used a yeast display approach coupled with multiple rounds of enrichment by fluorescent-activated cell sorting (FACS) to select gp120 variants that bind to the inferred germline of IOMA (IOMA iGL). Results: Binding studies using enzyme-linked immunosorbent assays (ELISAs) and surface plasmon resonance (SPR) demonstrated that our novel gp120 immunogens bind to IOMA iGL with micromolar affinity. Conclusions: We will present the results of immunization experiments using these novel immunogens in mouse models.

Item Type:Article
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Nussenzweig, Michel0000-0003-0592-8564
Bjorkman, Pamela0000-0002-2277-3990
Additional Information:© 2018 Mary Ann Liebert, Inc., publishers. Published Online: 22 Oct 2018.
Issue or Number:S1
Record Number:CaltechAUTHORS:20181116-085049231
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90949
Deposited By: Tony Diaz
Deposited On:16 Nov 2018 17:02
Last Modified:16 Nov 2021 03:37

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