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  • CD binding to gp causes a large scale

    2022-01-15

    CD4 binding to gp120 causes a large scale conformational change of gp120 which involves the gp120 core structure and the transitions of inner-domain layers (layer 1, 2 and 3), but also involves the movement of the major loops (V1, V2 and V3) [16], [17], [18], [19]. For instance, the V2-loop joins the bridging sheet formation with the C4 region β20-β21 hairpin of the outer-domain, and the V3-loop opens up to contact the coreceptor, CCR5 or CXCR4 [17], [18], [20]. A tryptophan residue at amino polycomb repressive complex position 375 (375W) of gp120 will fill the Phenylaniane-43 (Phe-43) cavity and stabilizes the gp120 into a CD4-bound conformation, but does not completely achieve the CD4-bound state [21], [22], [23]. More stabilization changes such as the addition of disulfides, salt-bridges added to the S375W conformation of the gp120 core structure have enhanced the stability and increased the immunogenicity [22], [24]. However, in respect to the outer-domain core structure only, we do not know whether the 375W can play a role in further improving the stability of the CD4-bound state. Here we have conducted the research into an outer-domain based HIV immunogen design. The antigenic nature of the CD4-BS has been recognized as conformation dependent because it is known to be located at the junction of three domains. Interestingly, the binding sites of some CD4-BS antibodies such as VRC01 or PGV04 are actually located on the outer domain, and the binding is almost independent from the inner domain and the bridging sheet. Since the outer-domain of gp120 is a relatively stable domain, it has become an ideal antibody target for vaccine immunogen design.
    Materials and methods
    Results
    Discussion This work again demonstrates that the CD4-BS of gp120 is an important region for antibody targeting, and the CD4-binding portion of the outer-domain appears to be even more imperative for antibody targeting. As has been documented, potent neutralizing antibodies such as VRC01 and PG04 are examples of targeting to this region. If we compare the whole gp120 to the outer-domain core as vaccine candidates, it is obvious that the outer-domain core has advantages in terms of molecular size, stability and epitope focusing. The outer-domain core structure avoids the unstable inner domain and the flexible loops which reduces the unwanted immunogenic face of the inner domain and focuses on the stable epitopes of VRC01-like antibodies. Therefore, we can see the outcomes of immunization data on the previous tested OD2 [18] and this research on OD3. It is possible that more specific neutralizing antibodies might be raised but less total antibodies were produced which suggests that non-neutralizing antibodies were reduced in the immunizations with OD2 and OD3. Based on this set of immunization data with OD1, OD2 and OD3, we can clearly see that the structure-based immunogen design has more rationale and accuracy for inducing specific neutralizing antibodies, which can be essentially explained by the epitope structural relationship between antigens and antibodies. We will continue to pursue this through investigations which purify the antibodies elicited from these immunizations. Then, we will examine their structures, binding epitopes and affinity, and compare to the known reference antibodies such as VRC01 and PG04. Thus, we may be able to gain more insights into the use of structure-based approaches to design more effective immunogens for HIV/AIDS vaccine development.
    Conclusions
    Acknowledgments This work was supported by the Bill and Melinda Gates Foundation, the NCV Seed grant and ARD Strategic grant to SHX. DH, DB and WW performed the experiments; SHX designed the immunogens; SHX and DH wrote the manuscript; DB, JT and MW helped with data analysis and reviewed the manuscript. We would like to thank Dr. Javier Seravalli in the Department of Biochemistry for helping with CD spectra analysis in the protein core facility.
    Introduction