Cell's important finding: The presence of type I natural antibodies similar to 2G12 antibodies in the human body may become a new target for HIV-1 vaccines

Written by | Original editor | A variety of pathogens, including the envelope protein of HIV [1], yeast [2] (Hall and Gow, 2013), and the surface of the spike protein of SARS-CoV-2 (Watanabe et al.
, 2020) All have glycosylation modification
.

Antibodies that recognize glycosylation in the body are a series of natural antibodies that existed before the body was stimulated by the same type of antigen
.

They exist in different subtypes and provide the body with the first line of defense against external bacterial, fungal and viral infections [3] (Holodick et al.
, 2017)
.

In the human body, natural antibodies produce mutant antibodies or some unknown changes after being stimulated by antigens, such as the way IgM antibodies change in pre-immune B cells [3].
It is currently assumed to be B cells from the marginal zone or transitional period [3] 4]
.

The envelope protein (Env) of HIV-1 (HIV-1) has severe glycosylation, and the recognition of epitopes recognized by the broadly neutralizing antibody (bnAb) by antibodies is restricted [1] (Cao et al.
al.
, 2017)
.

The bnAb of HIV-1 Env can approach the Env protein epitope through the long complementarity determining region (CDR) loop, but at the same time it also reaches a certain balance with the surrounding polysaccharides, which affects the neutralization effect [5]
.

Therefore, researchers have been looking for antibodies specifically against polysaccharides, trying to turn this effective defense against HIV-1 into its weakness [6]
.

However, the polysaccharides present in HIV-1 and other pathogens are also present in the host molecule [7].
Therefore, antibodies induced by pathogen polysaccharides may be inhibited by the body's immune tolerance
.

In previous studies, the 2G12 antibody is the only example that specifically binds HIV-1 Env proteoglycan [8]
.

The 2G12 antibody has a relatively short CDR3 loop and a unique heavy chain variable region (VH) domain interchange (Figure 1)
.

Among them, the exchange of two antibody binding fragments (Fab) forms a dimerized multivalent surface of Fab, which has strong Env surface polysaccharide binding ability [9]
.

The Fab dimerization of the 2G12 antibody has been shown to play a vital function in binding to HIV-1, which makes it stand out from ordinary polysaccharide-binding antibodies with weaker binding capacity
.

The affinity of bnAb 2G12 with HIV-1 is about nM, mainly because it can multivalently recognize a unique polysaccharide cluster [10]
.

The results of x-ray crystallography, negative stain electron microscopy and cryo-electron microscopy (cryo-EM) jointly demonstrated the 2G12 antibody VH domain exchange and Fab dimerization, as well as its multiple polysaccharide binding sites [11]
.

These two characteristics are crucial to its high affinity binding to HIV-1 Env
.

In addition to HIV-1 Env, 2G12 can also bind to Candida albicans, because it has a similar mannose motif with HIV-1 Env polysaccharide [12]
.

Recently, the teams of Wilton B.
Williams, Priyamvada Acharya and Barton F.
Haynes of Duke University Vaccine Research Institute, Duke University Department of Medicine and Immunology and other units published a titled Fab-dimerized glycan-reactive antibodies are astructural category on Cell.
of natural antibodies, in which the author reported multiple Fab-dimerized glycan-reactive (FDG) HIV-1 Env antibodies with natural Fab dimerization, which have a type I conformation similar to 2G12.
Different from the Y-shaped conformation of ordinary antibodies
.

However, they do not require the exchange of VH domains to neutralize HIV-1
.

In addition to recognizing yeast and HIV-1 Env polysaccharides, FDG antibody can also recognize the S2 subunit of the spike protein of SARS-CoV-2
.

First, the author used a glycosylated polypeptide (Man9-V3) to mimic the natural HIV-1 Env trimer to immunize rhesus monkeys, and then isolated four DH717 lineage antibodies DH717.
1 and DH717 from their plasma.
.
2, DH717.
3 and DH717.
4
.

These antibodies can recognize the recombinant Env soluble trisomy of HIV-1, Candida albicans and Cryptococcus neoformans, and have a stronger affinity than the 2G12 antibody
.

Their recognition of Man9-V3 is based on its polysaccharide motif rather than the polypeptide sequence itself
.

Under the negative staining electron microscope (NSEM), it can be seen that the three antibody subtypes DH717.
1, DH717.
2, and DH717.
4 have the classic Y-type and special I-type two conformations
.

The type I conformation, which is similar to the conformation of the 2G12 antibody, is formed due to the dimerization of Fab and is called FDG (Fab-dimerized glycan-reactive, FDG) antibody
.

It's just that the two Fab regions of the 2G12 antibody are juxtaposed on the same plane relative to the Fc, while the two Fab fragments of the H717 I antibody are not on the same plane relative to the Fc, but are deflected by an angle of 90°
.

At the same time, this FDG antibody does not have the VH domain interchange phenomenon similar to 2G12
.

Subsequently, this result was verified by the analysis of the crystal structure
.

It also explains that the dimerization of Fab is mediated by several mechanisms, including disulfide bonds, hydrophobic interactions and hydrogen bonds formed between Fab-Fab
.

Among them, the additional disulfide bond formed at the C74 position relative to ordinary antibodies dominates the dimerization of Fab and the formation of the I-type conformation
.

Subsequently, the authors used transcriptome sequencing to group and trace the B cells in the blood of rhesus monkeys, and found that the B cells that produce this type I antibody that binds to polysaccharides exist before immunization, and at least they mature and expand after being stimulated.
Increase
.

This phenomenon has also been verified in the human body
.

Precursor FDG antibodies have been isolated from HIV-1 seronegative humans, and they are present in the marginal zone B cells of IgM+IgD+CD27+
.

It shows that this kind of antibody also exists naturally in the human body
.

This research result may provide a new target for HIV-1 vaccine research
.

The author only tested the reactivity of this FDG antibody to recombinant HIV-1 Env and SARS-CoV-2 S proteoglycans, but this may exclude other types of polysaccharide forms in the body
.

The article tested the precursor FDG antibodies in the peripheral blood of 9 individuals who were not infected with HIV-1.
In the future, individuals and other immune organizations that need to be in a larger group will conduct more in-depth research on the information of these Abs
.

Original link: https://doi.
org/10.
1016/j.
cell.
2021.
04.
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