Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG

Abstract

We have tested three human monoclonal antibodies (MAbs) IgG1b12, 2G12, and 2F5) to the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1), and a tetrameric CD4-IgG molecule (CD4-IgG2), for the ability to neutralize primary HIV-1 isolates from the genetic clades A through F and from group O. Each of the reagents broadly and potently neutralized B-clade isolates. The 2F5 MAb and the CD4-IgG2 molecule also neutralized strains from outside the B clade, with the same breadth and potency that they showed against B-clade strains. The other two MAbs were able to neutralize a significant proportion of strains from outside the B clade, although there was a reduction in their efficacy compared with their activity against B-clade isolates. Neutralization of isolates by 2F5 correlated with their possession of the LDKW motif in a segment of gp41 near the membrane-spanning domain. The other two MAbs and CD4-IgG2 recognize discontinuous binding sites on gp120, and so no comparison between genetic sequence and virus neutralization was possible. Our data show that a vaccine based on the induction of humoral immunity that is broadly active across the genetic clades is not impossible if immunogens that express the epitopes for MAbs such as 2F5, 2G12, and IgG1b12 in immunogenic configurations can be created. Furthermore, if the three MAbs and CD4-IgG2 produce clinical benefit in immunotherapeutic trials in the United States or Europe, they may also do so elsewhere in the world.

Identifying epitopes of HIV-1 that induce protective antibodies

“…An exception is the human monoclonal antibody IgG1b12, which was constructed using recombinant technology from the bone marrow of an HIV-1-infected donor 49 . This monoclonal antibody has exceptionally broad activity against primary isolates, thereby confirming the crucial role of the CD4bd in HIV-1 infection 32,50 . Given the complexity of the CD4bd and the paucity of CD4bd-specific monoclonal antibodies with neutralizing activity, the design of an immunogen that will give rise to neutralizing antibodies specific for this epitope will be a challenge.…”

“…So, with the exception of clades B and E, which show distinct antigenic differences 121 , there seems to be no particular preference for sera from patients infected with one clade to neutralize other viruses from the same clade; a diagramatic representation of this is shown in FIG. 5. Similarly, studies of HIV-1-specific human monoclonal antibodies, most of which come from clade-B-infected individuals (such as those listed in TABLE 1) show their comparable potency in neutralizing many viruses from various clades 32,86,122 . These data raise important questions about the relevance of HIV-1 genotypic classification in vaccine design.…”

“…However, only a small minority of gp41-specific antibodies have neutralizing activity. One human monoclonal antibody, 2F5, has been shown to have broad neutralizing activity for diverse primary HIV-1 isolates 32 . This monoclonal antibody recognizes a core epitope of six amino acids within a relatively conserved 16-amino-acid linear sequence (NEQEL-LELDKWASLWN) in the ectodomain of gp41 near the transmembrane region of the molecule 33 .…”

Characterization of a monoclonal antibody to a novel glycan-dependent epitope in the V1/V2 domain of the HIV-1 envelope protein, gp120

“…Four new findings derive from these studies. First, we show that antibodies to GDEs in the V1/V2 domain of gp120 can result from immunization with recombinant gp120, whereas previously such antibodies have been isolated only from HIV-infected humans or chimpanzees (Walker et al, 2009(Walker et al, , 2011Bonsignori et al, 2011;Trkola et al, 1995;Vijh-Warrier et al, 1996;Wu et al, 1995). Second, we show that antibodies to GDEs can result from a relatively short immunization schedule and that continuous exposure to gp120 over a long period of time, as occurs during chronic HIV infection, is not required to elicit antibodies to GDEs.…”

Structural definition of a conserved neutralization epitope on HIV-1 gp120

“…Although gp120 is the primary target of neutralizing antibodies elicited during natural infection 23 , most gp120-reactive antibodies are ineffective at neutralizing primary HIV-1 isolates (reviewed in refs 4, 24). Only two gp120-reactive antibodies (b12, 2G12) with effective neutralization activity against diverse primary HIV-1 isolates have thus far been identified [25][26][27] . In vivo, b12 can protect macaques against vaginal challenge from pathogenic simian-human immunodeficiency virus (SHIV) 28 .…”