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 1

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Protective efficacy following intraperitoneal injection of selected rota...
Protective efficacy following intraperitoneal injection of selected rotavirus-specific mAb’s. BALB/c female mice (three mice per group) were intraperitoneally injected with mAb’s (3 mg/d) twice a day starting 2 days prior to 102 ID50 ECw challenge (see Methods). Treatment continued until day 7 after challenge. Fecal virus shedding for each mouse was detected by ELISA, and the area under the 7-day antigen shedding curve was calculated. Figure shows the mean percentage reduction of virus shedding for each group + SEM. *Percentage reduction in these 7D9-inoculated groups was significantly different from that in non–7D9-inoculated groups (P < 0.05). Results represent two separate experiments.