Abstract
HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.
Highlights
The HIV-1 envelope glycoprotein (Env) is essential for virus entry into target cells to establish infection
We summarize the data on the structure and function of neutralizing antibodies targeting gp41 heptad repeat region 1 (HR1), fusion peptide (FP) and membrane-proximal external region (MPER) and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env
The problematic of gp41 HR1 access and MPER broadly neutralizing antibodies (bnAbs) auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination
Summary
The HIV-1 envelope glycoprotein (Env) is essential for virus entry into target cells to establish infection. The development of new technologies that allow the identification and isolation of bnAbs from donors whose serum has been identified to have potent and broadly neutralizing activity have revolutionized the field [16] This led to the discovery of a plethora of antibodies targeting many exposed regions of the prefusion Env trimer and in turn accelerated the Viruses 2020, 12, 1210; doi:10.3390/v12111210 www.mdpi.com/journal/viruses. Understanding the role somatic hypermutation in the generation ofimmunogens broadly neutralizing structures of bnAbs target V1/V2 [19,20,21], glycan-V3 [22,23,24], the CD4-binding site [25,26,27,28,29], the fusion. Epitope composed of the linear high levels of somatic mutations, bnAb glycan recognition or accommodation and polyreactivity [42– Understanding these have important implications for MPER-based vaccine development. Weprinciples review the structural principles of bnAbs targeting gp, with a specific focus on MPERspecific antibodies, their bipartite epitope composed of the linear MPER epitope and specific and
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