A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1

Abstract

Vaccination against human immunodeficiency virus type 1 (HIV-1) requires an immunogen which will elicit a protective immunity against viruses that show a high degree of genetic polymorphism. Therefore, the identification of neutralizing epitopes which are shared by many strains would be useful. In previous studies, we established a human monoclonal antibody (2F5) that neutralizes a variety of laboratory strains and clinical isolates of HIV-1. In the present report, we define the amino acid sequence Glu-Leu-Asp-Lys-Trp-Ala (ELDKWA) on the ectodomain of gp4l as the epitope recognized by this antibody. The sequence was found to be conserved in 72% of otherwise highly variable HIV-1 isolates. Escape mutants were not detected in cells infected with HIV-1 isolates MN and RF in the presence of antibody 2F5. Since sequence variability of neutralizing epitopes is considered to be a major obstacle to HIV-1 vaccine development, the conserved B-cell epitope described here is a promising candidate for inclusion in a vaccine against AIDS.

Interfacial pre-transmembrane domains in viral proteins promoting membrane fusion and fission

“…Only two broadly neutralizing anti-HIV-1 antibodies isolated from peripheral blood mononuclear cells of HIV infected nonsymptomatic patients have been described to react with gp41 [95,96]. These antibodies, designated as 2F5 and 4E10, recognize epitopes within the conserved PreTM domain (reviewed in Refs.…”

Plant made anti-HIV microbicides—A field of opportunity

“…MAb 2F5 displays a broader neutralisation activity than 2G12, inhibiting HIV isolates from clades A, B, D and E (Binley et al, 2004). It docks onto to the core epitope ELDKWA on the lipid embedded membrane proximal exterior region (MPER) of gp41 and potentially interferes with the fusion step of the virus (Binley et al, 2004;de Rosny et al, 2004;Franquelim et al, 2011;Muster et al, 1993). On its own and in combination with other antibodies including 2G12 and 4E10, 2F5 displayed the ability to protect against an intravenous, vaginal and oral challenge of SHIV in macaques (Baba et al, 2000;Hessell et al, 2010;Mascola et al, 1999Mascola et al, , 2000.…”

Assessment of antibody responses against gp41 in HIV-1-infected patients using soluble gp41 fusion proteins and peptides derived from M group consensus envelope

“…The third highly immunoreactive peptide (656-670: QEKNE-QELLALDKWA) was found in a region that overlaps cluster II (designated a.a. 644-663 on HxB2: RLIEESQNQQEKNEQEL-LAL; (Binley et al, 1996)). This peptide contains residues "ALDKWA", which is the core epitope for mAb 2F5 (ELDKWA) (Muster et al, 1993) and not considered to be a part of cluster II (Binley et al, 1996;Goudsmit et al, 1990). The fact that a peptide just upstream of it (652-666: SQNQQEKNEQELLAL) is recognized by none of the patient plasma indicates critical participation of and/or contribution from residues "DKWA" in forming the correct conformation of epitope(s) within the peptide.…”

“…Antisera that exhibit broadly neutralizing activity against diverse HIV-1 isolates have been observed in some long-term non-progressors (LTNP) (Braibant et al, 2006;Cecilia et al, 1999;Pilgrim et al, 1997). However, they are rare; despite over two decades of AIDS research, only a handful of broadly reactive Nabs (BR-Nabs) have been identified, including monoclonal antibodies (mAbs) b12, 2G12, 447-52D, 2F5, 4E10 and m48 (Gorny et al, 1992;Muster et al, 1993;Roben et al, 1994;Stiegler et al, 2001;Trkola et al, 1996;Zhang et al, 2006;Zwick et al, 2001). While the first three antibodies are gp120-specific, the latter three target gp41.…”

“…Monoclonal antibodies 2F5 and 4E10 target adjacent, but distinct, linear epitopes in a highly conserved region of gp41 near the viral membrane known as the membrane-proximal external region (MPER) (Muster et al, 1993;Stiegler et al, 2001;Zhang et al, 2006;Zwick et al, 2001), a determinant that plays a critical role in HIV-1 fusion with the cell membrane (Salzwedel et al, 1999;Suarez et al, 2000). Epitope mapping studies of 2F5 with synthetic peptides (Barbato et al, 2003;Biron et al, 2002;Joyce et al, 2002), phage displayed peptide libraries (Menendez et al, 2004;Muster et al, 1993;Zwick et al, 2001), and protease protection assays (Parker et al, 2001) have identified ELDKWA as the core antibody binding site. 4E10 binds primarily to the hexapeptide NWFNIT, which lies just four amino acids downstream of the 2F5 epitope (Brunel et al, 2006;Cardoso et al, 2005;Stiegler et al, 2001;Zwick et al, 2001).…”