Structural Basis for the Recognition of Human Cytomegalovirus Glycoprotein B by a Neutralizing Human Antibody


Human cytomegalovirus (HCMV) belongs to the family of β-herpes viruses. HCMV infections are not only life threatening to people with a compromised immune system but also the most common viral cause of congenital defects in newborns. Hence, the development of HCMV vaccines was ranked top priority by the US Institute of Medicine in 1999. Virtually all infected individuals develop antibodies against the envelope protein gB, which plays a crucial role in the infection process. Here, we describe the crystal structure of a fragment of the virus neutralizing antibody SM5-1 in complex with an antigenic determinant of gB, namely Dom-II. The structure shows that antigen antibody interactions are concentrated within two CDRs of SM5-1. Computational methods and an analysis of additional antibody sequences from the same lineage reveal that additional key contributions to high affinity binding are provided by residues that stiffen the extra-long CDR H3 loop without directly contacting the antigen. We suggest that the optimization of such indirect contributions represents a common and yet undervalued principle of the antibody maturation process. Furthermore our data suggest that the neutralizing effect of SM5-1 either originates from blocking membrane fusion or from preventing interaction of gB with other envelope proteins.


Vyšlo v časopise: Structural Basis for the Recognition of Human Cytomegalovirus Glycoprotein B by a Neutralizing Human Antibody. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004377
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004377

Souhrn

Human cytomegalovirus (HCMV) belongs to the family of β-herpes viruses. HCMV infections are not only life threatening to people with a compromised immune system but also the most common viral cause of congenital defects in newborns. Hence, the development of HCMV vaccines was ranked top priority by the US Institute of Medicine in 1999. Virtually all infected individuals develop antibodies against the envelope protein gB, which plays a crucial role in the infection process. Here, we describe the crystal structure of a fragment of the virus neutralizing antibody SM5-1 in complex with an antigenic determinant of gB, namely Dom-II. The structure shows that antigen antibody interactions are concentrated within two CDRs of SM5-1. Computational methods and an analysis of additional antibody sequences from the same lineage reveal that additional key contributions to high affinity binding are provided by residues that stiffen the extra-long CDR H3 loop without directly contacting the antigen. We suggest that the optimization of such indirect contributions represents a common and yet undervalued principle of the antibody maturation process. Furthermore our data suggest that the neutralizing effect of SM5-1 either originates from blocking membrane fusion or from preventing interaction of gB with other envelope proteins.


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