Abstract
Oligomannose-type glycans on HIV-1 gp120 form a patch that is targeted by several broadly neutralizing antibodies (bnAbs) and that therefore is of interest to vaccine design. However, attempts to elicit similar oligomannose-specific bnAbs by immunizing with oligomannosidic glycoconjugates have only been modestly successful so far. A common assumption is that eliciting oligomannose-specific bnAbs is hindered by B cell tolerance, resulting from the presented oligomannosides being sensed as self molecules. Here, we present data, along with existing scientific evidence, supporting an additional, or perhaps alternate, explanation: serum mannosidase trimming of the presented oligomannosides in vivo. Mannosidase trimming lessens the likelihood of eliciting antibodies with capacity to bind full-sized oligomannose, which typifies the binding mode of existing bnAbs to the oligomannose patch. The rapidity of the observed trimming suggests the need for immunization strategies and/or synthetic glycosides that readily avoid or resist mannosidase trimming upon immunization and can overcome possible tolerance restrictions.
Highlights
Development of an effective HIV vaccine is still a high priority[1,2]
We evaluated the ability of broadly neutralizing antibodies (bnAbs) PGT128 and three related members of the PGT128/130 bnAb family to bind this new CRM197 glycoconjugate, which was named NIT211
In contrast to our observations with the conjugates, in vitro incubation of sera with SOSIP trimers showed no trimming of glycans comprising the oligomannose patch, demonstrating that these oligomannose-type glycans, unlike those presented on glycoconjugates, may be protected from mannosidase trimming
Summary
Development of an effective HIV vaccine is still a high priority[1,2]. One of the central challenges remains the creation of a formulation that elicits broadly neutralizing antibodies (bnAbs) to the HIV envelope spike (Env). Serum mannosidase trimming has been reported to occur fairly rapidly (t1⁄2 ~5–6 h)[21,22]; if so, that would readily decrease the availability of full-sized oligomannosides for recognition by B cells at priming and subsequent antibody affinity maturation in germinal centers[24] The significance of such enzymatic trimming is substantial given that bnAbs to the oligomannose patch on HIV gp[120] are specific for full-sized oligomannose[9,25,26,27,28] and considering that glycans are a major component of the epitope of many other bnAbs. Here, we report on our own investigation of serum mannosidase as an additional potential hurdle to eliciting oligomannose-specific bnAbs. First, we show that bnAb PGT128, an example of the newer generation of bnAbs to the oligomannose patch, binds substantially worse to a microtiter plate-bound glycoconjugate that has been incubated in situ with mammalian sera, with sera from mice and humans notably causing the greatest reduction. In addition to having obvious implications for the design of glycoconjugates for eliciting oligomannose-specific bnAbs, we show that our findings are of relevance to efforts employing recombinant envelope glycoproteins
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