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Computer-guided Dissection of the Structural Elements of Anti-HIV-1 gp120 V3 Monoclonal Antibodies
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Computer-guided Dissection of the Structural Elements of Anti-HIV-1 gp120 V3 Monoclonal Antibodies. |
| 개인저자 | Kamau, Edwin. |
| 단체저자명 | New York University. Basic Medical Science. |
| 발행사항 | [S.l.]: New York University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 123 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085678544 |
| 학위논문주기 | Thesis (Ph.D.)--New York University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Kong, Xiang-Peng. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | The V3 region of HIV-1 gp120 is among the most extensively studied regions of the viral envelope due to its role in viral entry, principal determination of chemokine receptor use. Its apex (the V3 crown) is highly immunogenic, eliciting about half of antibody responses in infected and vaccinated individuals. Consequently, human anti-V3 mAbs from HIV-1 infected individuals and vaccinees have been investigated to establish their potency, breadth, mechanism of neutralization, and immunoglobulin (Ig) gene usage. Additionally, crystal structures of some of anti-V3 mAbs in complex with V3 crown peptides have been solved, allowing the dissection of the atomic level antigen-antibody interactions. First, we used a combination of computational mutagenesis and modeling in tandem with fluorescence polarization (FP) assays to dissect the functional role of anti-V3 mAb 447-52D (447) long heavy chain complementarity determining region (CDRH3) and the contribution of individual CDRH3 apex residues to its affinity. We found that 447 CDRH3 length provides a large binding surface area and the best enthalpic contributions derived from hydrophobic packing, main-chain hydrogen bonds, electrostatic, and van der Waals interactions. We also found out that CDRH3 residue Try100I is critical to 447 binding affinity. Second, we performed computational-guided comparative structural analysis on the crystal structures of VH5-51/VL and VH1-3/VL3-10 encoded mAbs to determine the structural basis of the observed preferential bias usage of VH5-51 gene segment for anti-V3 mAbs. Our study revealed that both antibody sets target the V3 crown epitopes using a similar binding mode but a different docking approach. Importantly they both recognize two conserved V3 crown elements, Lys305 and Pro313, using germline-encoded residues. We found out that the VH5-51/VL mAbs are predicted to bind the conserved V3 crown elements with a higher affinity than the VH1-3/VL3-10 counterparts. Therefore, the VH5-51/VL encoded naive B cell receptors are better able to outcompete other VH families that also recognize the V3 crown to seed the germinal center (GC). Our findings can guide the design of future V3-focused immunogens to specifically target the naive VH5-51 B-cell receptor. |
| 일반주제명 | Pharmacology. Biochemistry. Bioinformatics. |
| 언어 | 영어 |
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