Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS

Abstract

Previously we identified the highly conserved amino acids Glu-Leu-Asp-Lys-Trp-Ala (ELDKWA) on the ecto-domain of gp41 as the epitope of a neutralizing monoclonal antibody (2F5) directed against human immunodeficiency virus type 1. In the present study, the sequence defining the epitope was introduced into the loop of antigenic site B of the influenza virus hemagglutinin. The resulting chimeric virus was able to elicit ELDKWA-specific immunoglobulins G and A in antisera of mice. Moreover, the distantly related human immunodeficiency virus type 1 isolates MN, RF, and IIIB were neutralized by these antisera. These data suggest that this conserved B-cell epitope is a promising candidate for inclusion in a vaccine against AIDS. The results also show that influenza virus can be used to effectively present the antigenic structure of this B-cell epitope.

Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D

“…In contrast, Bonsignori et al examined the interaction of CH01 to CH04, antibodies that recognize a complex epitope involving elements of the second and third variable regions (V2 and V3 loops) of the gp120 subunit, including an N-linked glycan at position 160, and reported that a very limited number of Envs bind the predicted germline form of this Ab (14). Also, Ma et al reported that the germline forms of MAbs 2F5 and 4E10, which target epitopes located in the membrane proximal external region (MPER) of the gp41 subunit (36,37), recognize two distinct recombinant Envs once they have been enzymatically deglycosylated (38). Overall, all currently available information suggests that recombinant Env proteins are poorly suited for engaging the predicted germline forms of bNAbs that target the CD4-BS but are relatively better suited to engage the predicted germline forms of bNAbs targeting conserved epitopes outside the CD4-BS.…”

Identification of a new epitope for HIV‐neutralizing antibodies in the gp41 membrane proximal external region by an Env‐tailored phage display library

“…Consequently, only a few neutralizing mAbs targeting gp41 are known. Most prominent are the broadly neutralizing patient-derived mAbs 2F5, 4E10, and Z13, targeting the MPER region of gp41 in the context of the viral membrane [19,[63][64][65][66][67][68][69]. Recently, a new mAb, CAP206-CH12, targeting an MPER epitope overlapping with the 4E10 epitope was identified by Ag-specific B-cell sorting [7].…”

Identifying epitopes of HIV-1 that induce protective antibodies

“…However, this region of gp41 -especially the core epitope that is recognized by monoclonal antibody 2F5 (ELDKWA) -seems to be poorly immunogenic, as antibodies specific for this epitope occur infrequently in HIV-1-infected individuals 39,40 . Moreover, experimental immunogens that consisted of the 2F5 epitope inserted into either the influenza virus haemagglutinin antigen, the hepatitis B virus surface antigen or the Escherichia coli MaIE protein failed to elicit antisera with neutralizing activity for primary isolates [40][41][42] . Therefore, this interesting epitope seems to require a particular molecular context, but this context might reduce the efficiency of its presentation to the immune system.…”