Neutralizing Antibodies Targeting HIV-1 gp41

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.

Unique genotypic features of HIV-1 C gp41 membrane proximal external region variants during pregnancy relate to mother-to-child transmission via breastfeeding

“…MPER targeting bn-HIV-Abs show outstanding breadth by neutralizing over 90% of viral strains on multiclade panels [ 19 , 22 , 24 , 26 , 27 ]. Although MPER targeting bn-HIV-Abs arose independently from different individuals infected by various clades [ 19 , 22 , 24 , 26 , 28 ], their epitopes overlap extensively, suggesting epitope conservation, immunogenesis, and antibody accessibility and supporting vaccine efforts [ 29 – 32 ]. Elevated maternal antibody titers to HIV-1 envelope ( env ) gp41 and/or gp120 epitopes are directly associated with perinatal MTCT [ 33 – 37 ].…”

A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target

“…It is a challenging epitope for immunogen design since bnAbs against this site typically recognize both a lipid component from the viral membrane and a transient Env conformation via long CDR loops [ 87 ]. Nevertheless, numerous antibodies against this highly conserved region have been identified: DH511 [ 88 ], 4E10 [ 87 , 89 ], 10E8 [ 90 ], 2F5 [ 91 ], VRC42 [ 92 ], LN01 [ 93 ], PGZL1 [ 94 ], Z13E [ 95 ], and CAP206-CH12 [ 96 ], and reviewed elsewhere [ 70 , 97 ]. No new bnAb structures against this epitope have been reported since.…”

“…Moreover, 1C2 is similar to gp120–gp41 interface bnAbs 3BC176 and 3BC315 in its ability to destabilize Env [ 50 , 76 , 98 ]. BnAbs have also been identified in a variety of fusion peptide-vaccinated animal models [ 99 , 100 ], and their structures have been reviewed previously [ 97 ]. While it is promising that immunization can produce bnAbs, it remains to be seen whether these responses can be recapitulated in non-human primates and whether they can withstand viral challenge.…”

The current and future role of nanovaccines in HIV-1 vaccine development

“…Much of the work with this type of nanovaccines has focused on the presentation of different peptides or proteins to the host immune system to increase their immunogenicity [81]. One of the major goals has been the induction of antibodies to the MPER region of gp41 because bnAbs have been recovered from infected individuals, which bind not only to the protein but also to the viral envelope [104][105][106]. Studies that included either the entire gp41 subunit or MPER peptides on the surface of liposomes resulted in the higher titers of antibodies than peptide or protein by itself and could induce weak to moderate levels of neutralization with some cross reactivity [66,107,108].…”