Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120
A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for s...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 30; pp. E2083 - E2090 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
24.07.2012
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. |
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| AbstractList | A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. Author Summary The signature residues we have identified for PVL antibodies suggest a common pathway for the development of potent CD4bs antibodies beginning with heavy chains derived from the VH1-2 germ-line gene segment. This pathway may represent the most likely way that PVL antibodies can develop in humans, as evidenced by their independent isolation from five different individuals. The near requirement for these antibodies to be derived from the VH1-2 gene segment has implications for testing antigens designed to elicit PVL-like antibodies in animals: Namely, animals that lack a suitable germ-line gene will likely fail to generate this class of antibody. Thus, alternative testing platforms would be preferable for raising PVL antibodies, such as transgenic mice incorporating the human Ig locus. Moreover, the identification of signature residues critical for PVL potency allows classification of CD4bs antibodies by sequence and is relevant for structure-based design efforts to improve the potency and breadth of anti-CD4bs antibodies as more efficacious anti-AIDS therapeutics. To determine whether changes in these signature PVL residues affected germ-line antibody binding to gp120, we conducted binding studies using mutated germ-line heavy chains paired with a mature light chain. We found that mutation of the signature heavy-chain residues reduced or abolished binding to the HIV-1 envelope protein, consistent with the PVL characteristic residues playing a key role in binding to the HIV-1 envelope and in triggering an initial immune response. Only 4 of ∼69 possible human germ-line V H gene segments include all of the PVL signature residues (VH1-2, VH1-45, VH1-58, and VH1-68). Studies of V gene use show that VH1-2 is >10-fold more common than the next most frequent germ-line segment containing all PVL signature residues (VH1-58), thus rationalizing the common germ-line V H gene segment origin of known PVLs. Of relevance to efforts to raise PVL antibodies in animals commonly used in research, we note that mouse, rabbit, and rat genomes do not include V H gene segments with the combination of Trp50 HC , Arg71 HC , and Asn58 HC . Crystal structures reveal that the new CD4bs antibodies bind to gp120 by mimicking CD4 ( 2 , 4 , 5 ). Available structural information, taken together with the large amount of sequence data for CD4bs antibodies ( 2 , 3 ), allows analyses to determine which of the antibodies bind gp120 in essentially the same manner and the critical sequence features that permit this binding. On the basis of inspections of alignments of antibody variable domain sequences, we found the following sequence characteristics of the most potent CD4bs antibodies: within the heavy chain, complete conservation of the amino acid residues Arg71 HC , Trp50 HC , Asn58 HC , and Trp100B HC , and within the light chain, conservation of Glu96 LC and a complementarity-determining region 3 length of exactly 5 aa residues. The heavy-chain sequence characteristics are found in CD4bs antibodies that descended from the VH1-2 germ line, but not from the VH1-46 germ line ( 3 ). The structural roles that Arg71 HC , Trp50 HC , Asn58 HC , and Trp100B HC play in the V H domain structure and in binding to the CD4bs on gp120 are shown schematically in Fig. P1 . We propose a nomenclature to describe antibodies that include this set of sequence characteristics: PVL antibodies, reflecting the first of this class to be isolated ( 1 ). A series of antibodies that recognize the CD4bs of HIV-1 gp120 were recently isolated ( 1 – 3 ). Binding of the HIV-1 envelope glycoprotein gp120 to the human cell surface receptor CD4 is the first step in infecting a cell, and thus this critical binding site is a potential vulnerability of the virus. Some of the new CD4bs antibodies, e.g., VRC01, NIH45-46, 3BNC117, VRC-PG04, and VRC-CH31, are remarkable for their broad neutralizing activity (neutralizing ∼90% of strains) and potency. For an antigen to elicit a strong antibody response, it has to be recognized initially by membrane-bound antibodies on naive B cells. During a sustained immune response, B-cell clones expressing these germ-line antibodies hypermutate so that a subset of B cells expresses antibodies with higher affinities for the original antigen. This process is called somatic hypermutation or affinity maturation, and it results in mutations in both the heavy and light chains of the antibody. Interestingly, despite being isolated from different donors, the new CD4bs antibodies arose from two closely related germ-line IgV H genes (VH1-2 and VH1-46) ( 3 ). A large number of antibodies targeting the CD4-binding site (CD4bs) on the HIV-1 envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with resistance to PVL antibodies. The lack of genes encoding these features in commonly used laboratory animals suggests that attempts to test vaccines designed to induce these antibodies need to be performed in mice genetically engineered to express human antibody genes. These results bear on both vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. A large number of anti-HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human VH gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies. [PUBLICATION ABSTRACT] |
| Author | Diskin, Ron West, Anthony P Bjorkman, Pamela J Nussenzweig, Michel C |
| Author_xml | – sequence: 1 fullname: West, Anthony P – sequence: 2 fullname: Diskin, Ron – sequence: 3 fullname: Nussenzweig, Michel C – sequence: 4 fullname: Bjorkman, Pamela J |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22745174$$D View this record in MEDLINE/PubMed |
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| Notes | http://dx.doi.org/10.1073/pnas.1208984109 Contributed by Pamela J. Bjorkman, May 30, 2012 (sent for review May 2, 2012) Author contributions: A.P.W. designed and performed research; A.P.W., R.D., and P.J.B. analyzed data; and A.P.W., M.C.N., and P.J.B. wrote the paper. |
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| Snippet | A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These... A large number of anti-HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These... |
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| SubjectTerms | Amino Acid Sequence antibodies Base Sequence Binding sites Biological Sciences CD4 Antigens - genetics CD4 Antigens - metabolism Conserved Sequence - genetics crystal structure Genes Germ Cells - immunology Glycoproteins HIV HIV Antibodies - genetics HIV Antibodies - immunology HIV Antibodies - metabolism HIV Envelope Protein gp120 - genetics HIV Envelope Protein gp120 - immunology HIV-1 Human immunodeficiency virus Human immunodeficiency virus 1 humans Molecular Sequence Data Mutagenesis Mutation Rate Neutralization Tests PNAS Plus Sequence Alignment Sequence Analysis, DNA Surface Plasmon Resonance vaccine development |
| Title | Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120 |
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