![]() The development of the well-ordered, soluble BG505 SOSIP.664 Env trimer ushered in a new era of HIV-1 spike mimetics (for review, see Sanders and Moore, 2017). To elicit such bNAbs by vaccination, a major effort is to design soluble mimetics that faithfully recapitulate structural features of the viral spike. Remarkably, such bNAbs can neutralize diverse clinical strains but arise sporadically during the course of natural infection and usually after 2 or more years ( McCoy and Burton, 2017). The HIV-1 surface-exposed functional Env spike is the sole virally encoded target for broadly neutralizing antibodies (bNAbs). This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. ![]() Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge.
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