A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans
Hye Young Kim, … , Dale T. Umetsu, Sergio D. Rosenzweig
Hye Young Kim, … , Dale T. Umetsu, Sergio D. Rosenzweig
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1111-1118. https://doi.org/10.1172/JCI44182.
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Research Article

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

Abstract

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.

Authors

Hye Young Kim, María Belén Eyheramonho, Muriel Pichavant, Carlos Gonzalez Cambaceres, Ponpan Matangkasombut, Guillermo Cervio, Silvina Kuperman, Rita Moreiro, Krishnamurthy Konduru, Mohanraj Manangeeswaran, Gordon J. Freeman, Gerardo G. Kaplan, Rosemarie H. DeKruyff, Dale T. Umetsu, Sergio D. Rosenzweig

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Figure 1

TIM1 polymorphisms affect HAV binding and uncoating.

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TIM1 polymorphisms affect HAV binding and uncoating. (A) The TIM-1–...
(A) The TIM-1–Fc fusion protein constructs used. Soluble TIM-1 fusion protein constructs containing the TIM-1 IgV domain and different lengths of the mucin domain were generated. The constructs contained the TIM-1 IgV domain and (a) the first 19 residues of the mucin domain (TIM-1[1–145]–Fc); (b) the first 42 residues of the mucin domain without the 157insMTTTVP insertion polymorphism (TIM-1[1–173]–Fc); (c) the entire mucin allele without the 157insMTTTVP insertion polymorphism (Short TIM-1–Fc); and (d) the entire mucin allele containing the 6-amino-acid insertion polymorphism (157insMTTTVP) (Long TIM-1–Fc). A Fc fusion protein containing the extracellular domain of the poliovirus receptor (PVR-Fc) with 3 Ig-like domains (V1, C1, and C2) was used as a negative control. (B) The long form of TIM-1 binds HAV more effectively than the shorter form. HAV was treated with the purified soluble fusion proteins described in A, which resulted in HAV neutralization. Residual HAV infectivity was determined by end-point ELISA titration assay in African green monkey kidney cells, and expressed as log10 of TCID50 ± SD (***P < 0.001 [ANOVA]). Lower infectivity indicates more effective binding of HAV to the designated TIM-1 form.