Identification of Aleutian Mink Disease Parvovirus Capsid Sequences Mediating Antibody-Dependent Enhancement of Infection, Virus Neutralization, and Immune Complex Formation

Abstract

Aleutian mink disease parvovirus (ADV) causes a persistent infection associated with circulating immune complexes, immune complex disease, hypergammaglobulinemia, and high levels of antiviral antibody. Although antibody can neutralize ADV infectivity in Crandell feline kidney cells in vitro, virus is not cleared in vivo, and capsid-based vaccines have proven uniformly ineffective. Antiviral antibody also enables ADV to infect macrophages, the target cells for persistent infection, by Fc-receptor-mediated antibody-dependent enhancement (ADE). The antibodies involved in these unique aspects of ADV pathogenesis may have specific targets on the ADV capsid. Prominent differences exist between the structure of ADV and other, more-typical parvoviruses, which can be accounted for by short peptide sequences in the flexible loop regions of the capsid proteins. In order to determine whether these short sequences are targets for antibodies involved in ADV pathogenesis, we studied heterologous antibodies against several peptides present in the major capsid protein, VP2. Of these antibodies, a polyclonal rabbit antibody to peptide VP2:428-446 was the most interesting. The anti-VP2:428-446 antibody aggregated virus particles into immune complexes, mediated ADE, and neutralized virus infectivity in vitro. Thus, antibody against this short peptide can be implicated in key facets of ADV pathogenesis. Structural modeling suggested that surface-exposed residues of VP2:428-446 are readily accessible for antibody binding. The observation that antibodies against a single target peptide in the ADV capsid can mediate both neutralization and ADE may explain the failure of capsid-based vaccines.

High Mutant Frequency in Populations of a DNA Virus Allows Evasion from Antibody Therapy in an Immunodeficient Host

“…G436 is immediately underneath T437, but the introduction of a Glu side chain at position 436 may severely disrupt the local conformation and the interaction with the antibody. Major epitopes have been found also in the equivalent capsid region of other related parvoviruses (5,6,39,51,56,62). In this regard, our observations with MVMi indicate that this antigenic loop can tolerate drastic changes without major alterations of parvovirus pathogenicity.…”

“…Several members of the Parvoviridae, a family of viruses with a single-stranded DNA (ssDNA; 5-kb) genome packaged into a 25-nm-diameter icosahedral capsid (45), cause persistent and chronic diseases in animals and immunocompromised humans that are often treated by passive immu-notherapy (2,5,38). Persistent parvovirus B19 infection of anemic and human immunodeficiency virus type 1-immunodepressed patients is commonly treated with antisera (31,38), and the generalized use of MAbs is also being recommended in this case (30).…”

Structure of Adeno-Associated Virus Serotype 5

“…A knowledge of antibody recognition domains across AAV serotypes could be important for designing vectors that evade neutralizing antibodies. This concept was recently highlighted by the work of Bloom and colleagues with ADV (8). Specifically, they found that neutralizing antibodies on surface-exposed residues of ADV could block receptor-mediated binding while enhancing antibody-mediated infection of macrophages.…”

Caspase Cleavage of the Nonstructural Protein NS1 Mediates Replication of Aleutian Mink Disease Parvovirus

“…Protein A conjugated with horseradish peroxidase was used to detect mink immunoglobulin (Ig) in a Western blot. Rabbit anti-NS1 (residues 173 to 464) antisera and a pool of anti-ADV VP2 monoclonal antibodies were also used in Western blot analysis (5). Additional rabbit anti-NS1 polyclonal antisera used for the immunolocalization of NS1 fusion proteins were R3810 raised against NS1 peptides 2 to 61 and R3125 raised against NS1 peptides 587 to 641.…”