Expression profiles of genes associated with viral entry in HCV‐infected human liver

Nakamuta, Makoto; Fujino, Tatsuya; Yada, Ryoko; Aoyagi, Yoko; Yasutake, Kenichiro; Kohjima, Motoyuki; Fukuizumi, Kunitaka; Yoshimoto, Tsuyoshi; Harada, Naohiko; Yada, Masayoshi; Kato, Masaki; Kotoh, Kazuhiro; Taketomi, Akinobu; Maehara, Yoshihiko; Nakashima, Mitsuyoshi; Enjoji, Munechika

doi:10.1002/jmv.22042

Cited by 20 publications

(22 citation statements)

References 34 publications

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“…However, both increased and decreased expression of viral entry receptors can occur upon HCV infection, potentially enhancing or blockading HCV entry into infected cells (6,(45)(46)(47)(48). Regardless of any effects on viral receptors, when a secondary replicon is "supertransfected" into cells already containing an HCV replicon, it replicates very poorly, clearly showing that postentry superinfection exclusion exists (7,34).…”

Section: Discussionmentioning

confidence: 99%

Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus

Webster

Ott

Greene

2013

J Virol

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Cells that are productively infected by hepatitis C virus (HCV) are refractory to a second infection by HCV via a block in viral replication known as superinfection exclusion. The block occurs at a postentry step and likely involves translation or replication of the secondary viral RNA, but the mechanism is largely unknown. To characterize HCV superinfection exclusion, we selected for an HCV variant that could overcome the block. We produced a high-titer HC-J6/JFH1 (Jc1) viral genome with a fluorescent reporter inserted between NS5A and NS5B and used it to infect Huh7.5 cells containing a Jc1 replicon. With multiple passages of these infected cells, we isolated an HCV variant that can superinfect cells at high levels. Notably, the superinfectious virus rapidly cleared the primary replicon from superinfected cells. Viral competition experiments, using a novel strategy of sequencebarcoding viral strains, as well as superinfection of replicon cells demonstrated that mutations in E1, p7, NS5A, and the poly(U/ UC) tract of the 3= untranslated region were important for superinfection. Furthermore, these mutations dramatically increased the infectivity of the virus in naive cells. Interestingly, viruses with a shorter poly(U/UC) and an NS5A domain II mutation were most effective in overcoming the postentry block. Neither of these changes affected viral RNA translation, indicating that the major barrier to postentry exclusion occurs at viral RNA replication. The evolution of the ability to superinfect after less than a month in culture and the concomitant exclusion of the primary replicon suggest that superinfection exclusion dramatically affects viral fitness and dynamics in vivo. In superinfection exclusion, a cell productively infected with a specific virus becomes resistant to infection with a homologous virus. This process has been described for several viruses, including human immunodeficiency virus (HIV) (1), Sindbis virus (2), duck hepatitis B virus (3), and citrus tristeza virus (4), in a broad range of hosts. Cells infected with or actively replicating hepatitis C virus (HCV) also become refractory to further HCV infection (5, 6). The superinfection block occurs at the level of translation or replication of the incoming secondary viral RNA (5-7), which is similar to the case of the related pestivirus bovine diarrhea virus (8). The exact mechanism is unclear. Since HCV RNA levels quickly plateau in infected cells in vitro, a superinfection block at the level of RNA translation or replication suggests that access to the necessary host factor(s) is rate limiting. This has clear implications for HCV treatment. By definition, a rate-limiting host factor is critical for the replication of the virus and may be a unique target in future therapies.Superinfection exclusion itself also has clear implications for treating HCV infection. Since viral recombination requires a host cell to be productively replicating two genomes, superinfection exclusion would be expected to effectively prevent viral recombination. If, howeve...

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Section: Discussionmentioning

confidence: 99%

Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus

Webster

Ott

Greene

2013

J Virol

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“…Studying the expression profiles of genes involved in lipid metabolism and HCV entry in liver biopsies from HCV-infected patients with chronic hepatitis C, the group of Enjoji revealed that LDL-R gene expression was significantly suppressed in HCV-infected compared with normal liver, and inversely correlated to the serum content of LDL-associated cholesterol and HCV core protein [67, 68]. Interestingly, a positive correlation between LDL-R and SR-BI gene expression was observed only in HCV-infected livers.…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein Receptors and Lipid Enzymes in Hepatitis C Virus Entry and Early Steps of Infection

Pécheur

2012

Scientifica

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Viruses are obligate intracellular agents that depend on host cells for successful propagation, hijacking cellular machineries to their own profit. The molecular interplay between host factors and invading viruses is a continuous coevolutionary process that determines viral host range and pathogenesis. The hepatitis C virus (HCV) is a strictly human pathogen, causing chronic liver injuries accompanied by lipid disorders. Upon infection, in addition to protein-protein and protein-RNA interactions usual for such a positive-strand RNA virus, HCV relies on protein-lipid interactions at multiple steps of its life cycle to establish persistent infection, making use of hepatic lipid pathways. This paper focuses on lipoproteins in HCV entry and on receptors and enzymes involved in lipid metabolism that HCV exploits to enter hepatocytes.

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“…Some studies have found that viral receptors (claudin-1, NPC1L1, and CD81) are downregulated upon infection (12,49,50). However, another study reported upregulation of claudin-1 (51), and another found mixed effects (occludin and LDL-R downregulation; claudin-1 upregulation) (52). Regardless of the effects HCV infection has on viral receptor expression, a postentry block to further viral RNA replication has been well demonstrated in cells replicating HCV RNA (11,12,20,53).…”

Section: Discussionmentioning

confidence: 99%

Rapid Intracellular Competition between Hepatitis C Viral Genomes as a Result of Mitosis

Webster¹,

Wissing²,

Herker³

et al. 2013

J Virol

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). This process, termed superinfection exclusion, does not involve downregulation of surface viral receptors but instead occurs inside the cell at the level of RNA replication. The originally infecting virus may occupy replication niches or sequester host factors necessary for viral growth, preventing effective growth of viruses that enter the cell later. However, there appears to be an additional level of intracellular competition between viral genomes that occurs at or shortly following mitosis. In the setting of cellular division, when two viral replicons of equivalent fitness are present within a cell, each has an equal opportunity to exclude the other. In a population of dividing cells, the competition between viral genomes proceeds apace, randomly clearing one or the other genome from cells in the span of 9 to 12 days. These findings demonstrate a new mechanism of intracellular competition between HCV strains, which may act to further limit HCV's genetic diversity and ability to recombine in vivo. Hepatitis C virus (HCV) is a positive-stranded, enveloped single-stranded RNA (ssRNA) virus in the Flavivirus family. Currently, HCV infects more than 180 million people worldwide, and the associated morbidity and mortality are second only to those caused by HIV among emerging infections (1). HCV is primarily transmitted parenterally, but vertical and sexual transmission may also occur. After acute infection, approximately 25% of patients spontaneously clear the virus. The remaining patients are chronically infected and may go on to develop hepatic steatosis, cirrhosis, and hepatocellular carcinoma (2).Complete in vitro replication of an HCV molecular clone was first demonstrated in 2005, using the genotype 2a virus JFH-1 (3-5). This clone, isolated from a Japanese male patient with fulminant hepatitis (6), replicated robustly in Huh7 cells and produced infectious virions in the absence of cell culture adaptive mutations. The availability of this infectious molecular clone provided a powerful experimental model with many advantages over the previously described HCV replicons (7). More recently, other groups have constructed highly infectious intergenotypic chimeras of JFH-1 and other HCV strains by making substitutions in the region from core to a portion of NS2 (8-10). The genotype 2a/2a chimera Jc1 is especially infectious (10).HCV blocks infection by other incoming HCV virions through a process known as superinfection exclusion (11,12). This process appears to occur after the virus enters the cell, which is different from the superinfection exclusion mechanism found in many other viral systems in which downregulation of cell surface viral receptors is involved. The intracellular superinfection block during HCV infection might result from competition between the primary and secondary viruses involving sequestration of key host factor(s) needed for viral replication or through occupancy of replicative niches on the endoplasmic reticulum (ER) membrane.Superinfection exclusion has clear implications for treating H...

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Expression profiles of genes associated with viral entry in HCV‐infected human liver

Cited by 20 publications

References 34 publications

Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus

Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus

Lipoprotein Receptors and Lipid Enzymes in Hepatitis C Virus Entry and Early Steps of Infection

Rapid Intracellular Competition between Hepatitis C Viral Genomes as a Result of Mitosis

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