A Potent Cross-Clade Neutralizing Human Monoclonal Antibody against a Novel Epitope on gp41 of Human Immunodeficiency Virus Type 1

Abstract

We have established a panel of human monoclonal antibodies against human immunodeficiency virus type 1 (HIV-1). The antibodies 2F5 and 2G12 have been identified to be two of the most potently in vitro neutralizing antibodies against HIV-1. Here we report on a further antibody, 4E10, of similar in vitro neutralizing potency. 4E10 binds to a novel epitope C terminal of the ELDKWA sequence recognized by 2F5, which has been so far the only described broadly neutralizing anti-gp41 antibody. Both 4E10 and 2F5 bind only weakly to infected cells compared with gp120-specific 2G12 and polyclonal anti-HIV-1 immunoglobulin (HIVIG), but show potent in vitro neutralizing properties. 4E10 neutralizes potently not only tissue culture-adapted strains but also primary isolates of different clades, including A, B, C, D, and E. Viruses that were found to be resistant to 2F5 were neutralized by 4E10 and vice versa; none of the tested isolates was resistant to both anti-gp41 antibodies. This confirms that the region recognized by 2F5 and 4E10 is essential for viral infectivity and may be important for vaccine design. Moreover, our results suggest that 4E10 should be further investigated for passive anti-HIV immunotherapy.

Identification and specificity of broadly neutralizing antibodies against HIV

“…The fifth class of bnAbs comprise those which target the MPER (Figure 2); namely 10E8, which was selected by single B‐cell culture and screening for neutralization36; and 2F5 and 4E10, which were isolated by a hybridoma approach 16, 18, 19, 81. The latter two Abs were isolated prior to PG9/16 and although they have quite extensive breadth are not as potent as most of the Abs described herein as bnAbs.…”

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…Nevertheless, rare potent monoclonal antibodies (mAbs) with broad neutralizing activity have been isolated from infected individuals. The two NAbs b12 and 2G12 are directed against exterior gp120 protein [7][8][9][10][11], and the three NAbs 2F5, 4E10 and Z13 are directed against the transmembrane gp41 protein [12][13][14]. Passive immunotherapy studies using combinations of some of these mAbs have resulted in protection against intravenous and/or mucosal simianhuman immunodeficiency virus (SHIV) challenge in monkeys [15][16][17][18], In addition, 2F5 and/ or 4E10 plus 2G12 immunotherapy have resulted in reduced viremia in established HIV-1 infection or delay of HIV-1 rebound in individuals undergoing interrupted antiretroviral treatment (ART) [19,20].…”

“…Among those, 2F5, 4E10 and Z13 recognize adjacent, but distinct linear epitopes within the C-terminal membrane proximal external region (MPER) of the HIV-1 gp41 protein [13,14]. The MPER is a highly conserved region among various HIV-1 isolates and is critical for HIV-1 mediated membrane fusion and infection [21,22].…”

The good and evil of complement activation in HIV-1 infection

“…46 Indeed, Abs with potent neutralizing activity against a broad range of HIV-1 strains across HIV-1 clades have been found in HIV-1-infected individuals. [54][55][56][57][58][59][60] Among these nAbs, 2G12, 2F5 and 4E10 are three of the most broadly used Abs cloned from HIV-1-infected patients. 54,55,57,58,[61][62][63][64] 2G12 recognizes a unique mannosedependent epitope within gp120, 55,61,[65][66][67] while binding sites of 2F5 and 4E10 lie within a well-defined region of the membrane-proximal external region of gp41.…”

“…[54][55][56][57][58][59][60] Among these nAbs, 2G12, 2F5 and 4E10 are three of the most broadly used Abs cloned from HIV-1-infected patients. 54,55,57,58,[61][62][63][64] 2G12 recognizes a unique mannosedependent epitope within gp120, 55,61,[65][66][67] while binding sites of 2F5 and 4E10 lie within a well-defined region of the membrane-proximal external region of gp41. 54,57,58,60,68 Passive immunization with a cocktail of these three human monoclonal Abs was effective in animal models, i.e., it conferred protection against intravenous, intravaginal or oral challenge with simian human immunodeficiency virus (a monkey HIV-1 analog) in rhesus macaques.…”