Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6–specific IgA mAb
Ningguo Feng, … , B.V. Venkataram Prasad, Harry B. Greenberg
Ningguo Feng, … , B.V. Venkataram Prasad, Harry B. Greenberg
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1203-1213. https://doi.org/10.1172/JCI14397.
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Article Immunology

Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6–specific IgA mAb

Abstract

Rotaviruses are the leading cause of severe diarrheal disease in young children. Intestinal mucosal IgA responses play a critical role in protective immunity against rotavirus reinfection. Rotaviruses consist of three concentric capsid layers surrounding a genome of 11 segments of double-stranded RNA. The outer layer proteins, VP4 and VP7, which are responsible for viral attachment and entry, are targets for protective neutralizing antibodies. However, IgA mAb’s directed against the intermediate capsid protein VP6, which do not neutralize the virus, have also been shown to protect mice from rotavirus infection and clear chronic infection in SCID mice. We investigated whether the anti-VP6 IgA (7D9) mAb could inhibit rotavirus replication inside epithelial cells and found that 7D9 acted at an early stage of infection to neutralize rotavirus following antibody lipofection. Using electron cryomicroscopy, we determined the three-dimensional structure of the virus-antibody complex. The attachment of 7D9 IgA to VP6 introduces a conformational change in the VP6 trimer, rendering the particle transcriptionally incompetent and preventing the elongation of initiated transcripts. Based on these observations, we suggest that anti-VP6 IgA antibodies confers protection in vivo by inhibiting viral transcription at the start of the intracellular phase of the viral replication cycle.

Authors

Ningguo Feng, Jeffrey A. Lawton, Joana Gilbert, Nelly Kuklin, Phuoc Vo, B.V. Venkataram Prasad, Harry B. Greenberg

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Figure 5

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(a) Contoured cross sections of mass density from the three-dimensional ...
(a) Contoured cross sections of mass density from the three-dimensional structures of native DLP (blue) and 7D9 DLP:IgA complex (red), viewed perpendicular to the icosahedral fivefold axis. Each contour represents a mass density difference of about 0.37 ς. The cross sections, labeled I–V, were extracted from radii between 261 Å and 325 Å (b). The upper panel of cross sections depicts the distribution of mass surrounding the mRNA release channel, with the icosahedral fivefold axis passing through the center. The lower panel of cross sections provides a close-up view of the mass distribution in one of the five trimers (indicated in the corresponding upper panel by a dashed box). The arrowheads in cross section III, lower panel, denote representative intermolecular interactions that are different in the two structures. Measurements of three specific mass translocations are also given. Scale bars, 50 Å. (b) Graphical representation of the radii from which cross sections were extracted in a. The cross sections are shown as semitransparent gray planes. The five VP6 trimers surrounding the mRNA release channel in the native DLP are colored in blue, and the underlying VP2 capsid layer is shown in green. (c) A portion of the surface representation of the native DLP, viewed along the icosahedral fivefold axis. The position of the fivefold axis along which the sections shown in a were taken is marked. The pair of VP6 trimers surrounding the twofold axis is also indicated.