VH1-69 antiviral broadly neutralizing antibodies: genetics, structures, and relevance to rational vaccine design

Abstract

Broadly neutralizing antibodies (bnAbs) are potential therapeutic molecules and valuable tools for studying conserved viral targets for vaccine and drug design. Interestingly, antibody responses to conserved epitopes can be highly convergent at the molecular level. Human antibodies targeting a number of viral antigens have often been found to utilize a restricted set of immunoglobulin germline genes in different individuals. Here we review recent knowledge on V_H1-69-encoded antibodies in antiviral responses to influenza virus, HCV, and HIV-1. These antibodies share common genetic and structural features, and often develop neutralizing activity against a broad spectrum of viral strains. Understanding the genetic and structural characteristics of such antibodies and the target epitopes should help advance novel strategies to elicit bnAbs through vaccination.

Figure 1. Recognition of influenza, HCV and HIV-1 envelope glycoproteins by representative antiviral V_H1–69 bnAbs.

(a+b) Binding of the influenza HA stem-specific CR9114 (a, PDB 4FQI) and RBS-specific F045–092 (b, PDB 4O58) bnAbs to the influenza HA-trimer. One HA protomer is colored in light pink and light purple for the HA1 and HA2 subunits, respectively. For clarity only one mAb is shown in each illustration. (c+d) Binding of AR3C to HCV E2 antigen region 3 (c, PDB 4MWF) and HC84–1 to E2434–446 peptide (d, PDB 4JZN) on the neutralizing face. The E2 front layer (FL) is colored in yellow and CD81 binding loop (CD81bl) in green. (e+f) Binding of 4E10 to HIV-1 membrane-proximal-external region (MPER) on gp41 (e, PDB 4XCF), and VRC13 to CD4 binding site (CD4bs) on HIV-1 gp120 that does not use a hydrophobic motif at the tip of CDRH2. (f, PDB 4YDJ). In each complex, the side chains of the hydrophobic residues at the tip of CDRH2 are shown in sticks and colored in red. The heavy chain (HC) and light chain (LC) CDRs that contribute to the binding are shown in a narrow tube representation.

Figure 2. V_H1–69 allelic polymorphism and heavy-chain CDR sequences of representative V_H1–69 antibodies.

(a) Polymorphic amino-acid residues encoded by V_H1–69 alleles. (b) Alignment of amino-acid sequences of the heavy-chain CDRs of representative V_H1–69 antibodies to viral antigens and their germline gene alleles. The hydrophobic motif in CDRH2 tip for each antibody is boxed in green (except for VRC13, which is polar and boxed in blue), the conserved tyrosine in CDRH3 is boxed in orange. Kabat numbering is indicated. The sequence logo shows the amino-acid composition at each position in CDR H1 and H2.