Research Project
9761441
In recent years there have been an increasing number of reports on broadly cross-reactive neutralizing antibodies (nAbs) with specificity for oligomannose-type glycans on the HIV envelope spike (Env). Immunization strategies that could yield such nAbs would therefore be desirable. One of the challenges faced by efforts to elicit oligomannose-specific nAbs is the host origin of the glycans, with immune tolerance mechanisms possibly limiting the frequency or development of B cells capable of producing Abs with specificity for mammalian oligomannose. For example, Abs elicited in typical experimental animals by glycoconjugate immunogens presenting oligomannosides are generally unable to bind oligomannose on Env and even when Env-binding Abs have been obtained, such as with recombinant yeast, they appear to bind insufficiently avid to the virus and fail to exert meaningful neutralizing activity. Here, we propose to utilize bacterially derived oligosaccharide analogs of oligomannose to overcome these challenges. We focus in this application on a fairly conserved patch of high-mannose glycans at and surrounding Asn301 and Asn332 on HIV gp120. Prototypic for Abs targeting these oligomannose-type glycans is the PGT128 family of Abs, which exhibit potent neutralizing activity. A vaccine component capable of eliciting similar nAbs could thus offer protection at even modest serum Ab titers. We not long ago discovered a bacterial oligosaccharide that closely resembles the D1 arm of mammalian oligomannose and subsequently made synthetic analogs of it with a D3 arm-like extension. One of these analogs, in the form of a neoglycoconjugate, is bound avidly by members of the PGT128 Ab family and their predicted germline predecessor. More crucially, preliminary data show that immunization of transgenic animals expressing an unarranged human Ab repertoire with this conjugate results in glycan- specific Abs with HIV tier 2 cross-neutralizing activity. Here, we propose to expand on these encouraging first results. Specifically, we seek to elaborate on our conjugate design and utilize transgenic animals to identify an optimal adjuvant+conjugate combination to maximize nAb responses. We also seek to dissect Ab responses at the serum and repertoire levels to compare similarities between the elicited and existing nAbs, which may inform boosting strategies. Finally, we propose to test our strategy in macaques to assess the extent to which it may work in outbred systems. In sum, this project will investigate whether glycan mimicry can serve to readily trigger the development of cross-reactive nAbs to the highly vulnerable oligomannose patch on HIV Env. If so, this work could inform strategies for targeting other glyco-epitopes on HIV-1.
