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J Clin Invest. 2019 Aug 12;130:3839-3851. doi: 10.1172/JCI128382. eCollection 2019 Aug 12.

Human VP8* mAbs neutralize rotavirus selectively in human intestinal epithelial cells.

Author information

1
Departments of Medicine and Microbiology and Immunology, School of Medicine, Stanford University, Stanford, California, USA.
2
VA Palo Alto Health Care System, Palo Alto, California, USA.
3
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
4
Department of Biochemistry, School of Medicine, Stanford University, Stanford, California, USA.
5
Berkeley Center for Structural Biology, Molecular Biophysics, and Integrated Bioimaging, Lawrence Berkeley Laboratory, Berkeley, California, USA.
6
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
7
Division of Infectious Disease, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
8
Institute of Veterinary Medicine, Jiangsu Academy of Agriculture Science, Nanjing, China.

Abstract

We previously generated 32 rotavirus-specific (RV-specific) recombinant monoclonal antibodies (mAbs) derived from B cells isolated from human intestinal resections. Twenty-four of these mAbs were specific for the VP8* fragment of RV VP4, and most (20 of 24) were non-neutralizing when tested in the conventional MA104 cell-based assay. We reexamined the ability of these mAbs to neutralize RVs in human intestinal epithelial cells including ileal enteroids and HT-29 cells. Most (18 of 20) of the "non-neutralizing" VP8* mAbs efficiently neutralized human RV in HT-29 cells or enteroids. Serum RV neutralization titers in adults and infants were significantly higher in HT-29 than MA104 cells and adsorption of these sera with recombinant VP8* lowered the neutralization titers in HT-29 but not MA104 cells. VP8* mAbs also protected suckling mice from diarrhea in an in vivo challenge model. X-ray crystallographic analysis of one VP8* mAb (mAb9) in complex with human RV VP8* revealed that the mAb interaction site was distinct from the human histo-blood group antigen binding site. Since MA104 cells are the most commonly used cell line to detect anti-RV neutralization activity, these findings suggest that prior vaccine and other studies of human RV neutralization responses may have underestimated the contribution of VP8* antibodies to the overall neutralization titer.

KEYWORDS:

Adaptive immunity; B cells; Vaccines; Virology

PMID:
31403468
PMCID:
PMC6715378
[Available on 2019-12-03]
DOI:
10.1172/JCI128382
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