Abstract
The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.
Highlights
A major roadblock in generating an effective HIV-1 vaccine has been the inability to elicit broadly neutralizing antibodies, capable of neutralizing a diverse variety of HIV-1 primary isolates, either during acute HIV-1 infections, or after immunization with various HIV-1 envelope (Env) immunogens [1,2,3,4]
We reasoned that tetramerization of the gp41 membrane proximal external region (MPER) 2F5 epitope would i) more physiologically mimic the multimeric nature of B cell receptors (BCR) interactions with antigens, and ii) allow us to identify B cells with a larger range of affinities for the 2F5 gp41 MPER epitope because of the increased avidity conferred by its multimerization
We show that the 2F5 epitope of the HIV-1 gp41 MPER interacts with BALB/c marginal zone (MZ) and B1 IgMa B cells in a manner that is distinct from traditional, clonal binding by IgMb B cells
Summary
A major roadblock in generating an effective HIV-1 vaccine has been the inability to elicit broadly neutralizing antibodies (bnAbs), capable of neutralizing a diverse variety of HIV-1 primary isolates, either during acute HIV-1 infections, or after immunization with various HIV-1 envelope (Env) immunogens [1,2,3,4]. Passive infusion of mixtures of 2F5, 4E10, 1b12 or 2G12 into rhesus monkeys protects against SHIV infection, providing hope that if these antibodies could be induced in man, a preventive HIV-1 vaccine might be possible [12,13] Two of these rare bnAbs, 2F5 and 4E10, interact with a attractive target for a B cell-based HIV-1 vaccine, the HIV-1 gp membrane proximal external region (MPER), in the neighboring linear, neutralizing core epitopes ELDKWA and NWFDIT, respectively [2,14,15,16,17,18,19,20,21,22]. There is evidence that the physiological form of the gp MPER to which 2F5 binds, the ‘‘prehairpin intermediate’’, is a unique structure that is only transiently expressed upon engagement of the CD4 receptor and chemokine co-receptors [11,28,29,30], implying that the repertoire of gp MPER bnAb-producing B cells is present, but the gp MPER pre-hairpin intermediate form is not available for a sufficient period of time to engage B cells
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