TIM1 (HAVCR1): an Essential “Receptor” or an “Accessory Attachment Factor” for Hepatitis A Virus?

Das, Anshuman; Maury, Wendy; Lemon, Stanley M.

doi:10.1128/jvi.01793-18

Cited by 18 publications

(18 citation statements)

References 10 publications

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“…In agreement with this, an overall less efficient surface attachment to host cells, independently of HSPGs or ITGA3, has been observed. Interestingly, the eHEV membrane contains phosphatidylserine (PS) which might bind cell surface receptor TIM-1 (T cell immunoglobulin mucin domain 1) on host cells and thereby serve as a potential attachment factor ( Figure 2 ), a mechanism that has been described for multiple other enveloped viruses with outer envelope leaflets enriched in PS [ 23 , 24 ]. However, whether this dual lifestyle of the HEV virion influences its survival, dissemination, and tissue tropism within the host remains unclear.…”

Section: Who Wants To Play? – Interplay Between Host Cell and Viral Fmentioning

confidence: 99%

Virus–Host Cell Interplay during Hepatitis E Virus Infection

Wissing

Brüggemann

Steinmann

et al. 2021

Trends in Microbiology

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The molecular interplay between cellular host factors and viral proteins is a continuous process throughout the viral life cycle determining virus host range and pathogenesis. The hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans worldwide. However, the mechanisms of liver pathology and clinical disease remain poorly understood for HEV infection. This review summarizes our current understanding of HEV–host cell interactions and highlights experimental strategies and techniques to identify novel host components required for the viral life cycle as well as restriction factors. Understanding these interactions will provide insight into the viral life cycle of HEV and might further help to devise novel therapeutic strategies and antiviral targets.

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Section: Who Wants To Play? – Interplay Between Host Cell and Viral Fmentioning

confidence: 99%

Virus–Host Cell Interplay during Hepatitis E Virus Infection

Wissing

Brüggemann

Steinmann

et al. 2021

Trends in Microbiology

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“…Thus, gangliosides mediate a late step in viral entry, likely within late endolysosomes. Previous studies show endocytosis of eHAV is driven at least in part by interactions with phosphatidylserine receptors such as TIM1 8 , 9 , whereas interactions of the capsid with cell surface sialoglycoproteins (possibly in addition to gangliosides) may mediate endocytosis of nHAV. nHAV is known to hemagglutinate type O erythrocytes in a neuraminidase- and pH-sensitive manner, and binds glycophorin A 17 , 18 .…”

mentioning

confidence: 97%

“…TIM1 (T cell immunoglobulin and mucin domain containing protein 1, a.k.a. HAVCR1) was reported previously to be an HAV receptor 7 , but it is not essential for infection and acts only as an attachment factor for quasi-enveloped virus by binding phosphatidylserine on the eHAV surface 8 , 9 . Also unknown is the trigger for capsid disassembly and whether this process is similar or different for the capsids of naked and quasi-enveloped virions once the eHAV membrane has been degraded.…”

mentioning

confidence: 99%

Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus

et al. 2020

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The Picornaviridae are a diverse family of positive-strand RNA viruses that includes numerous human and veterinary pathogens 1 . Among these, hepatitis A virus (HAV), a common cause of acute hepatitis in humans, is unique in that it is hepatotropic and released from hepatocytes without lysis in small vesicles resembling exosomes 2 , 3 . These quasi-enveloped virions (eHAV) are infectious and the only form of virus detected in blood during acute infection 2 . By contrast, non-enveloped, naked virions (nHAV) are shed in feces, stripped of membranes by bile salts during passage through bile ducts to the gut 4 . How these two distinct types of infectious hepatoviruses enter cells to initiate infection is enigmatic. Here we describe a genome-wide forward screen that identified glucosylceramide synthase (UGCG) and other components of the ganglioside synthetic pathway as crucial host factors required for cellular entry by hepatoviruses. We show that gangliosides, preferentially disialogangliosides, function as essential endolysosome receptors required for infection by both naked and quasi-enveloped virions. In the absence of gangliosides, both virion types are efficiently internalized through endocytosis, but capsids fail to uncoat and accumulate within LAMP1 + endolysosomes. Gangliosides relieve this block, binding the capsid at low pH and facilitating a late step in entry involving uncoating and delivery of the RNA genome to the cytoplasm. These results reveal an atypical cellular entry pathway for hepatoviruses that is unique among picornaviruses.

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“…Taken together with our previous work showing the direct interaction of HAV with HAVCR1 in cellular and cell-free systems (2)(3)(4)(5)(6)(7)(8)(9)(10), our data clearly indicated that HAVCR1 is indeed a functional HAV receptor of vpHAV and exo-HAV. For the letter to the editor of Das et al (11), the Lemon lab and Maury lab (Lemon/Maury labs) tried to reproduce our results using GL37 cells and one of the sgRNAs that we described in our paper (1) but used a flawed experimental design that led them to conclude incorrectly that HAVCR1 was not a functional vpHAV receptor. The Lemon/Maury lab data clearly show that the susceptibility of vpHAV is reduced significantly in their GL37 HAVCR1 KO cells compared to that in wild-type GL37 (GL37 wt) cells (see Fig.…”

mentioning

confidence: 99%

“…A) Schematic representation of the CRISPR/Cas9 strategies used to knock out the HAVCR1 gene at exon 2 in GL37 cells. The strategy used by Das et al(11) (Lemon/Maury labs) was based on a single sgRNA to introduce a single cut in exon 2 and generate small and undefined indels. A heterogeneous population of cells containing indels was used to assess the role of HAVCR1 as a functional HAV receptor.…”

mentioning

confidence: 99%

Reply to Das et al., “TIM1 (HAVCR1): an Essential ‘Receptor’ or an ‘Accessory Attachment Factor’ for Hepatitis A Virus?”

Costafreda

Kaplan

2019

J Virol

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W e have recently shown that HAVCR1 is a functional hepatitis A virus (HAV) cellular receptor in clone GL37 of African green monkey kidney (GL37) cells that mediates cell entry of viral particles (vpHAV) and exosomes produced in HAV-infected cells (exo-HAV or eHAV) (1). We also showed that HAVCR1 is the predominant HAV receptor in GL37 cells, whereas alternative, yet-unidentified HAV receptors are coexpressed with HAVCR1 in other primate cells, such as Vero E6 and Huh7 cells (1). The knockout (KO) of HAVCR1 using CRISPR/Cas9 technology significantly reduced the susceptibility of GL37 cells to HAV infection, which was regained upon transfection of HAVCR1 cDNA (1), supporting the notion that resistance to HAV infection in these GL37 HAVCR1 KO cells is due to the lack of HAV receptors rather than other factors. Taken together with our previous work showing the direct interaction of HAV with HAVCR1 in cellular and cell-free systems (2-10), our data clearly indicated that HAVCR1 is indeed a functional HAV receptor of vpHAV and exo-HAV. For the letter to the editor of Das et al. (11), the Lemon lab and Maury lab (Lemon/Maury labs) tried to reproduce our results using GL37 cells and one of the sgRNAs that we described in our paper (1) but used a flawed experimental design that led them to conclude incorrectly that HAVCR1 was not a functional vpHAV receptor. The Lemon/Maury lab data clearly show that the susceptibility of vpHAV is reduced significantly in their GL37 HAVCR1 KO cells compared to that in wild-type GL37 (GL37 wt) cells (see Fig. 1D and E in reference 11). However, the HAV background level in their GL37 HAVCR1 KO cells was ϳ200 times higher than in ours (1), which is likely due to a combination of factors, including the CRISPR/Cas9 strategy used to generate their HAVCR1 KO cells (Fig. 1A), the short vpHAV adsorption times, and the high multiplicities of infection used in their experiments. The Lemon/ Maury labs produced their GL37 HAVCR1 KO cells using a single sgRNA cloned into a lentivirus vector to mediate a single cut in exon 2 of the HAVCR1 gene, selected the pool of puromycin-resistant transduced cells, verified that heterogeneous small insertions and deletions (indels) were introduced in exon 2, and used the uncloned heterogeneous cell population to analyze the function of HAVCR1 as an HAV receptor. This simple and fast procedure resulted in the selection of a pool of heterogeneous puromycin-resistant cells consisting mainly of HAVCR1 KO cells but also most likely containing cells with various degrees of susceptibility to vpHAV infection due to (i) small in-frame indels that did not prevent the HAV receptor function of HAVCR1, (ii) off-target events that conferred puromycin resistance but did not knock out HAVCR1, and (iii) expression of different levels of alternative HAV receptors that are not predominant in AGMK GL37 cells compared to in Vero and Huh7 cells (1), which would significantly increase the background level of HAV infection in their heterogenous pool of puromycin-resistant cells. To circum...

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TIM1 (HAVCR1): an Essential “Receptor” or an “Accessory Attachment Factor” for Hepatitis A Virus?

Cited by 18 publications

References 10 publications

Virus–Host Cell Interplay during Hepatitis E Virus Infection

Virus–Host Cell Interplay during Hepatitis E Virus Infection

Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus

Reply to Das et al., “TIM1 (HAVCR1): an Essential ‘Receptor’ or an ‘Accessory Attachment Factor’ for Hepatitis A Virus?”

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