Interferon Lambda 4

Last updated

IFNL4
Identifiers
Aliases IFNL4 , IFNAN, interferon, lambda 4 (gene/pseudogene), interferon lambda 4 (gene/pseudogene)
External IDs OMIM: 615090; GeneCards: IFNL4; OMA:IFNL4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001276254

n/a

RefSeq (protein)

NP_001263183

n/a

Location (UCSC) Chr 19: 39.25 – 39.25 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Interferon lambda 4 (gene symbol: IFNL4) is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.

Contents

IFNL4 is similar to three neighboring genes (IFNL1, IFNL2 and IFNL3) in that proteins encoded by these genes bind to a shared co-receptor complex. Formation of this complex leads to activation of the JAK-STAT signalling pathway and upregulation of numerous interferon-stimulated genes. Genetics variants within or near this gene have been linked to clearance of hepatitis C virus (HCV) infection and other phenotypes.

Discovery

The first three interferon lambda genes were discovered in 2003 by two independent research groups that used different nomenclatures in their reports. [3] [4] In 2013, Prokunina-Olsson et al. reported the presence of a fourth gene in this region, which they discovered after treating human hepatocytes with polyinosinic:polycytidylic acid (poly I:C) to simulate HCV infection and induce expression of interferon lambda genes. RNA sequencing revealed the presence of IFNL4, which had been overlooked previously, in the interferon lambda region. [5]

In 2003, the Human Genome Organization Gene Nomenclature Committee (HUGO NC) had designated the first three genes found in this region as interleukins, but HUGO NC reconsidered that decision upon discovery of the fourth gene ten years later. Today, these four genes are recognized as interferon lambda genes, with official symbols of IFNL1 (formerly IL29), IFNL2 (formerly IL28A), IFNL3 (formerly IL28B) and IFNL4.

Structure

The interferon lambda genes lie in the 19q13.13 chromosomal region. IFNL4 is located between IFNL3 and IFNL2. The IFNL4 gene contains five exons and the full IFNL4 protein consists of 179 amino acids. [5]

The proteins encoded by the IFNL1, IFNL2, and IFNL3 genes have high amino-acid sequence similarity. [3] [4] IFNL2 and IFNL3 share ~96% amino-acid identity, and IFNL1 shares ~81% identity with IFNL2 and IFNL3. IFNL4 differs considerably from other members of this family. IFNL4 is most closely related to IFNL3, however, these proteins share only ~30% amino-acid identity. [5] Similarity between IFNL3 and IFNL4 is greatest for the A and F helices, where lambda interferons interact with the IFNLR1 receptor, and least in the D helix, where they interact with IL10R2, the second component of the interferon lambda receptor complex. [5]

Genetic variants

In 2009 (i.e., before the discovery of IFNL4), results from genome wide association studies (GWAS) indicated that single nucleotide polymorphisms (SNPs) near IFNL3 (rs12979860, rs8099917, and others) strongly associated with response to pegylated interferon-α and ribavirin treatment [6] [7] [8] and spontaneous clearance of hepatitis C virus (HCV) infection. [9] [10]

As the gene then known as IL28B was the closest known gene at the time, these genetic variants were called ‘IL28B variants’ and it was assumed that the observed associations reflected differences in the structure or regulation of that gene. However, discovery of IFNL4 revealed many of these variants to be within or nearest to IFNL4. The rs12979860 SNP is located within intron 1 of IFNL4, while rs8099917 lies in an intergenic region, but nearest to IFNL4. [5]

IFNL4 contains a polymorphism that controls the generation of the IFNL4 protein. The IFNL4-ΔG/TT (rs368234815, previously ss469415590) dinucleotide variant is composed of the rs11322783 (Δ/T) and rs74597329 (G/T) SNPs. Because those SNPs are in full linkage disequilibrium, rs368234815, rs11322783 and rs74597329 all provide the same information. In the NCBI dbSNP database, rs368234815 been merged into rs11322783. In the Genome Aggregation Database, however, IFNL4-ΔG/TT is represented by rs74597329. IFNL4-ΔG generates the complete IFNL4 protein while IFNL4-TT results in a frameshift that prematurely terminates the protein, producing truncated polypeptides without known biological function. [5]

Another functional polymorphism within IFNL4 alters the protein's biological function. A non-synonymous variant located in exon 2 (rs117648444) substitutes a serine for a proline at amino acid position 70 (P70S) when present on a haplotype that includes the IFNL4-ΔG allele. [5] In vitro studies have demonstrated the IFNL4 S70 protein has weaker biological function than IFNL4 P70. Specifically, IFNL4 S70 produced lower levels of interferon-stimulated gene expression and less antiviral activity compared to IFNL4 P70. [11]

Population genetics

Although the IFNL4 gene is present in all primates (and most non-primate mammals except mice or rats), humans are the only species in which the allele that abrogates IFNL4 has been found. [12]

The chromosomal region containing IFNL4 has undergone the strongest selection of any region that harbors an interferon gene. [13] Specifically, there has been very strong evolutionary selection for the IFNL4-TT variant, which ‘knocks out’ production of the IFNL4 protein. [14] This allele likely arose just before the out-of-Africa migration and underwent immediate selection in the African population. That selection strengthened in European and Asian populations. As a result, whereas ~95% of individuals of African ancestry carry at least one copy of the IFNL4-ΔG allele and are able to produce IFNL4, that percentage drops to ~50% in Europeans and <15% in Asians. [5] Comparison of African and East Asian populations revealed the IFNL4-TT allele to be among the most differentiated variants genome-wide. [14]

It is unlikely HCV infection exerted the selection pressure that created these striking differences, as HCV did not become common until the twentieth century, and chronic HCV infection has too long of a course to majorly impact reproduction. [15]

There is high linkage disequilibrium between the IFNL4-ΔG/TT variant and the rs12979860 and rs8099917 SNPs. [5] Linkage disequilibrium between IFNL4-ΔG/TT and IFNL4 rs12979860 is complete in Asian populations (r2=1.0) and strong among those of European (r2>0.9), but weaker in African populations (r2~0.7). [5] For rs8099917, linkage disequilibrium with IFNL4-ΔG/TT is strong in Asian populations, moderate in Europeans, and weak in Africans. [5]

The IFNL4-ΔG/TT and rs117648444 variants present in three observed haplotypes that can modify or abrogate the IFNL4 protein. These haplotypes are: IFNL4-ΔG: rs117648444-G, which creates the IFNL4 P70 protein; IFNL4-ΔG: rs117648444-A, which creates the IFNL4 S70 protein; IFNL4-TT: rs117648444-G, which does not generate a full IFNL4 protein. [5] [11]

Associated phenotypes

IFNL4 genetic variants are associated with a variety of phenotypes, including immune response to HCV infection, selection for HCV variants, hepatic inflammation and fibrosis, as well as certain opportunistic viral infections, and cancers.

HCV clearance

Genotype for the IFNL4-ΔG/TT variant (and SNPs in linkage disequilibrium with that polymorphism) associate with both spontaneous clearance of HCV infection and successful treatment of chronic hepatitis C.

Interferon lambda became a focus of HCV research when studies associated the rs12979860 and rs8099917 SNPs with response to pegylated interferon-α and ribavirin treatment for chronic hepatitis C, [6] [7] [8] and spontaneous HCV clearance. [9] [10] Compared to populations of European or Asian ancestry, African American populations demonstrated a lower frequency of the rs12979860-CC genotype, [6] [9] which is associated with viral clearance. That observation provided an explanation for previously observed racial differences in HCV treatment response and spontaneous clearance. [16] [17] The demonstrated association between genotype for the rs12979860 SNP and treatment led the US Food and Drug Administration to recommend testing for “IL28B” in clinical trials for new HCV treatments. [18] Studies have been predominantly conducted on HCV genotype 1, but the association between IFNL4 genotype and impaired HCV clearance has been observed for other HCV genotypes as well. [19] [20]

IFNL4-ΔG/TT is the likely primary functional variant that accounts for this association. High linkage disequilibrium between marker SNPs (e.g., rs12979860) and candidate explanatory genetic variants (e.g., IFNL4-ΔG/TT) present a challenge in identifying functional polymorphisms. However, weaker linkage disequilibrium between IFNL4-ΔG/TT and IFNL4 rs12979860 in populations of African ancestry facilitate comparison of those polymorphisms, and in African American populations IFNL4-ΔG/TT was shown to be a better predictor than rs12979860 for response to treatment with pegylated interferon-α/ribavirin therapy and spontaneous HCV clearance. [5] [21] These findings were confirmed in a larger study of spontaneous clearance in an African American population [22] and extended to European populations. [23] [24]

Associations between HCV clearance and genotype for the IFNL4-ΔG/TT polymorphism are strong. Among patients enrolled in the Virahep-C Trial, odds ratios for achieving a sustained virological response after treatment pegylated-interferon alpha/ribavirin (IFNL4-TT/TT versus IFNL4- ΔG/ΔG) were 2.90 in African-Americans and 4.42 in European-Americans. [5] In the HALT-C cohort, even larger odds ratios were observed for sustained virological response: 11.0 and 6.94 among African-Americans and European-Americans, respectively. [5]

Haplotypes that include the SNP (rs117648444),which controls the IFNL4 P70S protein variant, also associate with HCV clearance. In population studies, the variant that creates IFNL4 S70 associates with increased rates of spontaneous HCV clearance and better treatment response. [11] [25] In in vitro studies, the derived IFNL4 S70 protein produces reduced intrahepatic interferon stimulating gene expression and antiviral activity relative to IFNL4 P70. [11] These results provide additional evidence that reduced IFNL4 activity improves HCV clearance.

Selection for HCV variants

IFNL4 genotype may affect the HCV genome by selecting for certain viral strains, including those that lead to resistance to treatment. A genome-to-genome analysis revealed IFNL4 rs12979860 to be associated with variation for many amino acids in the HCV genome. HCV-infected patients with the rs12979860-CC genotype (i.e., those who do not generate the IFNL4 protein) had a higher frequency of non-synonymous HCV variants than patients with non-CC genotypes. [26]

Certain direct acting antiviral agents (DAAs) used to treat HCV infection target the HCV NS5A protein. HCV variants in which histidine is substituted for tyrosine at amino acid position 93 (NS5A Y93H) may cause resistance to those agents and decrease treatment success. Patients with the NS5A Y93H variant are less likely to respond to NS5A inhibitors such as daclatasvir, ledipasvir and ombitasvir, [27] [28] which are commonly used in popular DAA regimens (e.g., Harvoni). Patients with the IFNL4-TT/TT genotype were shown to have a higher frequency of the NS5A Y93H substitution than those who carried the ΔG allele. [29] Consistent with those results, the IFNL4 rs12979860-C/C genotype was strongly shown to be associated with the prevalence of the Y93H variant in patients infected with HCV genotype 1b. [30]

Hepatic inflammation and fibrosis

IFNL4 genotypes associated with increased HCV clearance and treatment response have also been linked to increased hepatic inflammation and fibrosis progression, which can lead to development of cirrhosis and liver cancer.

The rs8099917-G allele, which is in high linkage disequilibrium with IFNL4-ΔG and associates with reduced HCV clearance, has been associated with decreased necroinflammation, fibrosis and fibrosis progression. [31] Consistent with that finding, individuals with chronic hepatitis C and the rs12979860-CC genotype tended to display higher portal inflammation, although analysis of paired biopsy results did not reveal associations between this genotype and fibrosis progression. [32] Extending those findings, rs12979860-CC genotype was shown to be associated with increased inflammation and fibrosis not only in chronic HCV patients, but also in those with chronic hepatitis B or nonalcoholic fatty liver disease. [33]

Like with HCV, linkage disequilibrium poses a challenge in identifying the functional polymorphism for these associations. In a study of HCV-infected African Americans and European ancestry patients undergoing liver transplantation, donor genotype for IFNL4-ΔG/TT was a stronger predictor of post-transplant fibrosis progression than genotype for rs12979860. [34] However, in a second study on patients of European ancestry with chronic hepatitis C, [35] linkage disequilibrium between IFNL4-ΔG/TT, IFNL4 rs12979860 and another variant in IFNL3 3’ untranslated region (rs4803217) was too strong to discern genotype differences for hepatic inflammation and fibrosis. In contrast to results from studies of HCV clearance, no differences between genotypes that generated different variants of the IFNL4 protein (IFNL4 P70S) were found for either fibrosis or inflammation. [35]

Risk of cancer

GWAS have been conducted for a large range of malignancies. However, a GWAS association between IFNL4 genotype and cancer is limited to risk of a rare subtype of ovarian cancer. GWAS performed by an international consortium revealed the IFNL4-ΔG allele, which generates the IFNL4 protein, was associated with a decreased risk of mucinous ovarian carcinoma. [36] The explanation for this association remains to be determined.

In a candidate gene studies, associations with IFNL4 genotype have been reported for prostate cancer and Kaposi's sarcoma. IFNL4-ΔG associated with an increased risk of prostate cancer among men with sexually transmitted infections. [37] [38] In a Swiss cohort, men who carried the rs8099917-G allele, which is in linkage disequilibrium with IFNL4-ΔG in European populations, had an increased risk of Kaposi's sarcoma. [39]

Other infections

Studies on IFNL4 variants and other infectious diseases have yielded mixed results. In a European population, individuals who carry the IFNL4 rs12979860-T allele (and therefore generate IFNL4 protein) were found to have more episodes of severe herpes labialis, [40] which is caused by the herpes simplex virus. However, in a large cohort of HIV-infected women, genotype for the IFNL4-ΔG/TT polymorphism was not associated with herpes simplex virus-related outcomes, including episodes of oral or genital herpes. [41] Human cytomegalovirus (human betaherpesvirus 5) infection can be reactivated in patients who become immunocompromised after organ transplantation or due to advanced HIV infection. Homozygosity for IFNL4-ΔG has been linked to increased risk for cytomegalovirus retinitis in HIV patients. [42] Additionally, the IFNL4-ΔG allele has been associated with both higher rates of cytomegalovirus replication and more symptoms due to cytomegalovirus infection in both solid-organ [43] and stem cell transplant patients. [44]

Function

Interferon lambda proteins are signaling proteins involved in immune response to viral infection. These proteins are classified as type-III interferons because they use the IFNLR1 and IL10R2 receptors for signaling. Signaling initiated by IFNL or IFN-α triggers the JAK-STAT pathway, leading to the expression of numerous interferon-stimulated genes with anti-viral and anti-proliferative effects.

In contrast to the ubiquitous expression of receptors for IFN-α, IFNLR1 is largely restricted to tissues of epithelial origin. [3] [4] Therefore, interferon lambda proteins may have evolved specifically to protect the epithelium. In vitro studies have revealed that interferon-stimulated gene expression and anti-viral activity induced by recombinant IFNL4 are comparable to that induced by IFNL3, [45] however, the antiviral effects of IFNL4 have faster onset than those produced by other members of the interferon lambda family. [46]

Because interferons are generally considered to be antiviral cytokines and IFNL4 has demonstrated such anti-viral properties, it seems paradoxical that producing IFNL4 protein is linked to impaired clearance of HCV. [15] The explanation for this paradox is not fully understood.

Higher interferon stimulated gene expression associated with IFNL4 indicate that this protein does have in vivo antiviral effects, but, at least for HCV infection, other manifestations seem to override those influences. [47] While most interferon stimulated genes have antiviral effects, some may enhance viral replication. [48] IFNL4 induces expression of USP18 and ISG15, [49] which interfere with the function of IFN-α, [50] although it is not clear that this occurs in vivo during HCV infection. [47] SOCS1, another negative regulator of the immune response to viral infections, may also be induced by IFNL4. [46] It is possible that IFNL4 interferes with the antiviral activity of other interferons. There is evidence that IFNL4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of negative regulators of the interferon response and that IFNL4 acts faster than other type III IFNs in inducing such genes. [51] [46] [47]

The ability to produce IFNL4 (i.e., carriage of IFNL4 rs12979860 CT or TT genotype), in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV, which indicates that IFNL4 may be associated with T helper cell 2 (Th2) immune skewing. [52]

Research

Prior to the discovery of IFNL4, genotype for the rs12979860 SNP was used to predict response of HCV-infected patients to treatment with pegylated interferon-α/ribavirin therapy. Newer regimens based on combinations of DAAs are much more effective than pegylated interferon-α/ribavirin and testing for IFNL4 genotype is not currently recommended for those regimens. However, DAA regimens remain expensive. It could be cost effective to use IFNL4 genotype to predict response to shorter than standard duration treatment. Treatment duration could be personalized for individual patients or populations, such as for East Asians, who have a high frequency of the IFNL4-TT/TT genotype. [53]

Recent studies, primarily in mouse models, have demonstrated that other members of the interferon lambda family provide tissue barrier protection against a wide range of viral pathogens, including neuroinvasive West Nile virus infection, [54] respiratory infections including influenza [55] [56] [57] and gastrointestinal viruses such as norovirus [58] and rotavirus. [59] Given the strong evolutionary selection against the IFNL4 protein-generating IFNL4-ΔG allele, genotype for the IFNL4-ΔG/TT variant may play an important role in other infectious diseases, therefore, future epidemiological studies should examine those relationships.

Interferons are generally considered to be anti-viral cytokines that are generated in response to viral invasion. Results from studies of IFNL4 variants challenge that paradigm. IFNL4 has anti-viral properties in vitro, yet individuals who cannot generate this protein (homozygous for IFNL4-TT), are more likely to clear infection with HCV. Furthermore, nonalcoholic fatty liver disease is not caused by a viral infection, so this condition would not be expected to induce expression of interferons. Unexpectedly, IFNL4 genotype affects the development of hepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Future research aimed at understanding these paradoxes may further our understanding of interferon biology.

Notes

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Viral hepatitis</span> Liver inflammation from a viral infection

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).

<span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

Pegylated interferon alfa-2a, sold under the brand name Pegasys among others, is medication used to treat hepatitis C and hepatitis B. For hepatitis C it is typically used together with ribavirin and cure rates are between 24 and 92%. For hepatitis B it may be used alone. It is given by injection under the skin.

<span class="mw-page-title-main">CXCL10</span> Mammalian protein found in humans

C-X-C motif chemokine ligand 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the CXCL10 gene. C-X-C motif chemokine 10 is a small cytokine belonging to the CXC chemokine family.

Pegylated interferon alfa-2b is a drug used to treat melanoma, as an adjuvant therapy to surgery. Also used to treat hepatitis C, it is no longer recommended due to poor efficacy and adverse side-effects. Subcutaneous injection is the preferred delivery method.

The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. They were discovered in 2003. Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.

<span class="mw-page-title-main">ITPA</span> Protein-coding gene in the species Homo sapiens

Inosine triphosphate pyrophosphatase is an enzyme that in humans is encoded by the ITPA gene, by the rdgB gene in bacteria E.coli and the HAM1 gene in yeast S. cerevisiae; the protein is also encoded by some RNA viruses of the Potyviridae family. Two transcript variants encoding two different isoforms have been found for this gene. Also, at least two other transcript variants have been identified which are probably regulatory rather than protein-coding.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">Telaprevir</span> Chemical compound

Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

A hepatitis C vaccine, a vaccine capable of protecting against the hepatitis C virus (HCV), is not yet available. Although vaccines exist for hepatitis A and hepatitis B, development of an HCV vaccine has presented challenges. No vaccine is currently available, but several vaccines are currently under development.

<span class="mw-page-title-main">Alisporivir</span> Chemical compound

Alisporivir (INN), or Debio 025, DEB025, is a cyclophilin inhibitor. Its structure is reminiscent of, and synthesized from ciclosporin.

WGAViewer is a bioinformatics software tool which is designed to visualize, annotate, and help interpret the results generated from a genome wide association study (GWAS). Alongside the P values of association, WGAViewer allows a researcher to visualize and consider other supporting evidence, such as the genomic context of the SNP, linkage disequilibrium (LD) with ungenotyped SNPs, gene expression database, and the evidence from other GWAS projects, when determining the potential importance of an individual SNP.

<span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

<span class="mw-page-title-main">Interferon Lambda 3</span> Protein-coding gene in the species Homo sapiens

Interferon lambda 3 encodes the IFNL3 protein. IFNL3 was formerly named IL28B, but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly discovered IFNL4 gene. Together with IFNL1 and IFNL2, these genes lie in a cluster on chromosomal region 19q13. IFNL3 shares ~96% amino-acid identity with IFNL2, ~80% identity with IFNL1 and ~30% identity with IFNL4.

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.

<span class="mw-page-title-main">Beclabuvir</span> Chemical compound

Beclabuvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection that has been studied in clinical trials. In February 2017, Bristol-Myers Squibb began sponsoring a post-marketing trial of beclabuvir, in combination with asunaprevir and daclatasvir, to study the combination's safety profile with regard to liver function. From February 2014 to November 2016, a phase II clinical trial was conducted on the combination of asunaprevir/daclatasvir/beclabuvir on patients infected with both HIV and HCV. Furthermore, a recent meta-analysis of six published six clinical trials showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, asunaprevir, and beclabuvir irrespective of ribavirin use, prior interferon-based therapy, or restriction on noncirrhotic patients, IL28B genotype, or baseline resistance-associated variants

<span class="mw-page-title-main">Narlaprevir</span> Chemical compound

Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000272395 Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 3 Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. (January 2003). "IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology. 4 (1): 69–77. doi:10.1038/ni875. PMID   12483210. S2CID   2734534.
  4. 1 2 3 Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. (January 2003). "IL-28, IL-29 and their class II cytokine receptor IL-28R". Nature Immunology. 4 (1): 63–8. doi:10.1038/ni873. PMID   12469119. S2CID   35764259.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, et al. (February 2013). "A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus". Nature Genetics. 45 (2): 164–71. doi:10.1038/ng.2521. PMC   3793390 . PMID   23291588.
  6. 1 2 3 Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. (September 2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature. 461 (7262): 399–401. Bibcode:2009Natur.461..399G. doi:10.1038/nature08309. PMID   19684573. S2CID   1707096.
  7. 1 2 Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. (October 2009). "IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy". Nature Genetics. 41 (10): 1100–4. doi:10.1038/ng.447. PMID   19749758. S2CID   21619093.
  8. 1 2 Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. (October 2009). "Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C". Nature Genetics. 41 (10): 1105–9. doi:10.1038/ng.449. PMID   19749757. S2CID   20399078.
  9. 1 2 3 Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. (October 2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature. 461 (7265): 798–801. Bibcode:2009Natur.461..798T. doi:10.1038/nature08463. PMC   3172006 . PMID   19759533.
  10. 1 2 Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. (April 2010). "Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study". Gastroenterology. 138 (4): 1338–45, 1345.e1-7. doi:10.1053/j.gastro.2009.12.056. PMID   20060832. S2CID   25546833.
  11. 1 2 3 4 Terczyńska-Dyla E, Bibert S, Duong FH, Krol I, Jørgensen S, Collinet E, et al. (December 2014). "Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes". Nature Communications. 5: 5699. Bibcode:2014NatCo...5.5699.. doi: 10.1038/ncomms6699 . PMID   25534433.
  12. Paquin A, Onabajo OO, Tang W, Prokunina-Olsson L (January 2016). "Comparative Functional Analysis of 12 Mammalian IFN-λ4 Orthologs". Journal of Interferon & Cytokine Research. 36 (1): 30–6. doi:10.1089/jir.2015.0096. PMC   4722605 . PMID   26308395.
  13. Manry J, Laval G, Patin E, Fornarino S, Itan Y, Fumagalli M, et al. (December 2011). "Evolutionary genetic dissection of human interferons". The Journal of Experimental Medicine. 208 (13): 2747–59. doi:10.1084/jem.20111680. PMC   3244034 . PMID   22162829.
  14. 1 2 Key FM, Peter B, Dennis MY, Huerta-Sánchez E, Tang W, Prokunina-Olsson L, et al. (October 2014). Pritchard JK (ed.). "Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4)". PLOS Genetics. 10 (10): e1004681. doi: 10.1371/journal.pgen.1004681 . PMC   4199494 . PMID   25329461.
  15. 1 2 O'Brien TR, Prokunina-Olsson L, Donnelly RP (November 2014). "IFN-λ4: the paradoxical new member of the interferon lambda family". Journal of Interferon & Cytokine Research. 34 (11): 829–38. doi:10.1089/jir.2013.0136. PMC   4217005 . PMID   24786669.
  16. Muir AJ, Bornstein JD, Killenberg PG (May 2004). "Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites". The New England Journal of Medicine. 350 (22): 2265–71. doi: 10.1056/NEJMoa032502 . PMID   15163776.
  17. Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, et al. (August 2006). "Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1". Gastroenterology. 131 (2): 470–7. doi: 10.1053/j.gastro.2006.06.008 . PMID   16890601. S2CID   20296642.
  18. Pacanowski M, Amur S, Zineh I (May 2012). "New genetic discoveries and treatment for hepatitis C". JAMA. 307 (18): 1921–2. doi:10.1001/jama.2012.3516. PMID   22570460.
  19. Pedergnana V, Irving WL, Barnes E, McLauchlan J, Spencer CC (October 2019). "IFNL4 Genetic Variants on Sustained Virologic Response and Viremia in Hepatitis C Virus Genotype 3 Patients". Journal of Interferon & Cytokine Research. 39 (10): 642–649. doi:10.1089/jir.2019.0013. PMC   6767867 . PMID   31260374.
  20. Li Y, Yang L, Sha K, Liu T, Zhang L (December 2016). "Correlation of interferon-lambda 4 ss469415590 with the hepatitis C virus treatment response and its comparison with interleukin 28b polymorphisms in predicting a sustained virological response: a meta-analysis". International Journal of Infectious Diseases. 53: 52–58. doi: 10.1016/j.ijid.2016.10.023 . PMID   27810523.
  21. Aka PV, Kuniholm MH, Pfeiffer RM, Wang AS, Tang W, Chen S, et al. (February 2014). "Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus". The Journal of Infectious Diseases. 209 (3): 350–4. doi:10.1093/infdis/jit433. PMC   3883162 . PMID   23956438.
  22. Vergara C, Thio CL, Johnson E, Kral AH, O'Brien TR, Goedert JJ, et al. (April 2019). "Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus". Gastroenterology. 156 (5): 1496–1507.e7. doi:10.1053/j.gastro.2018.12.014. PMC   6788806 . PMID   30593799.
  23. Bibert S, Roger T, Calandra T, Bochud M, Cerny A, Semmo N, et al. (June 2013). "IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction". The Journal of Experimental Medicine. 210 (6): 1109–16. doi:10.1084/jem.20130012. PMC   3674704 . PMID   23712427.
  24. Franco S, Aparicio E, Parera M, Clotet B, Tural C, Martinez MA (January 2014). "IFNL4 ss469415590 variant is a better predictor than rs12979860 of pegylated interferon-alpha/ribavirin therapy failure in hepatitis C virus/HIV-1 coinfected patients". AIDS. 28 (1): 133–6. doi: 10.1097/QAD.0000000000000052 . PMID   24072198. S2CID   205980805.
  25. Galmozzi E, Aghemo A (April 2014). "Nonsynonymous variant Pro70Ser (rs117648444) in IFNL4 gene identifies carriers of the rs368234815 ΔG allele with higher HCV RNA decline during the first 4 weeks of pegylated interferon and ribavirin therapy in HCV-1 patients". Journal of Clinical Virology. 59 (4): 274–5. doi:10.1016/j.jcv.2014.01.006. PMID   24495847.
  26. Ansari MA, Pedergnana V, Ip LC, Magri A, Von Delft A, Bonsall D, et al. (STOP-HCV Consortium) (May 2017). "Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus". Nature Genetics. 49 (5): 666–673. doi:10.1038/ng.3835. PMC   5873514 . PMID   28394351.
  27. Karino Y, Toyota J, Ikeda K, Suzuki F, Chayama K, Kawakami Y, et al. (April 2013). "Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir". Journal of Hepatology. 58 (4): 646–54. doi:10.1016/j.jhep.2012.11.012. PMID   23178977.
  28. Lontok E, Harrington P, Howe A, Kieffer T, Lennerstrand J, Lenz O, et al. (November 2015). "Hepatitis C virus drug resistance-associated substitutions: State of the art summary". Hepatology. 62 (5): 1623–32. doi: 10.1002/hep.27934 . PMID   26095927.
  29. Akamatsu S, Hayes CN, Ochi H, Uchida T, Kan H, Murakami E, et al. (September 2015). "Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5A". Journal of Hepatology. 63 (3): 554–63. doi:10.1016/j.jhep.2015.03.033. PMID   25849245.
  30. Peiffer KH, Sommer L, Susser S, Vermehren J, Herrmann E, Döring M, et al. (January 2016). "Interferon lambda 4 genotypes and resistance-associated variants in patients infected with hepatitis C virus genotypes 1 and 3". Hepatology. 63 (1): 63–73. doi: 10.1002/hep.28255 . PMID   26406534. S2CID   25261511.
  31. Bochud PY, Bibert S, Kutalik Z, Patin E, Guergnon J, Nalpas B, et al. (February 2012). "IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes". Hepatology. 55 (2): 384–94. doi: 10.1002/hep.24678 . PMID   22180014. S2CID   29737102.
  32. Noureddin M, Wright EC, Alter HJ, Clark S, Thomas E, Chen R, et al. (November 2013). "Association of IL28B genotype with fibrosis progression and clinical outcomes in patients with chronic hepatitis C: a longitudinal analysis". Hepatology. 58 (5): 1548–57. doi:10.1002/hep.26506. PMC   3758382 . PMID   23703931.
  33. Eslam M, Hashem AM, Leung R, Romero-Gomez M, Berg T, Dore GJ, et al. (March 2015). "Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease". Nature Communications. 6: 6422. Bibcode:2015NatCo...6.6422.. doi:10.1038/ncomms7422. PMC   4366528 . PMID   25740255.
  34. Aiken T, Garber A, Thomas D, Hamon N, Lopez R, Konjeti R, et al. (2016-11-22). Booth DR (ed.). "Donor IFNL4 Genotype Is Associated with Early Post-Transplant Fibrosis in Recipients with Hepatitis C". PLOS ONE. 11 (11): e0166998. Bibcode:2016PLoSO..1166998A. doi: 10.1371/journal.pone.0166998 . PMC   5119817 . PMID   27875564.
  35. 1 2 Eslam M, McLeod D, Kelaeng KS, Mangia A, Berg T, Thabet K, et al. (May 2017). "IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis" (PDF). Nature Genetics. 49 (5): 795–800. doi:10.1038/ng.3836. hdl: 10026.1/9163 . PMID   28394349. S2CID   13736645.
  36. Kelemen LE, Lawrenson K, Tyrer J, Li Q, Lee JM, Seo JH, et al. (August 2015). "Genome-wide significant risk associations for mucinous ovarian carcinoma". Nature Genetics. 47 (8): 888–97. doi:10.1038/ng.3336. PMC   4520768 . PMID   26075790.
  37. Minas TZ, Tang W, Smith CJ, Onabajo OO, Obajemu A, Dorsey TH, et al. (2018). "IFNL4-ΔG is associated with prostate cancer among men at increased risk of sexually transmitted infections". Communications Biology. 1 (1): 191. doi:10.1038/s42003-018-0193-5. PMC   6235841 . PMID   30456312.
  38. Tang W, Wallace TA, Yi M, Magi-Galluzzi C, Dorsey TH, Onabajo OO, et al. (November 2018). "IFNL4-ΔG Allele Is Associated with an Interferon Signature in Tumors and Survival of African-American Men with Prostate Cancer". Clinical Cancer Research. 24 (21): 5471–5481. doi:10.1158/1078-0432.CCR-18-1060. PMC   6214748 . PMID   30012562.
  39. Bibert S, Wójtowicz A, Taffé P, Tarr PE, Bernasconi E, Furrer H, et al. (November 2018). "Interferon lambda 3/4 polymorphisms are associated with AIDS-related Kaposi's sarcoma" (PDF). AIDS. 32 (18): 2759–2765. doi:10.1097/QAD.0000000000002004. PMID   30234607. S2CID   52304642.
  40. Griffiths SJ, Koegl M, Boutell C, Zenner HL, Crump CM, Pica F, et al. (2013-08-08). Gao SJ (ed.). "A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication". PLOS Pathogens. 9 (8): e1003514. doi: 10.1371/journal.ppat.1003514 . PMC   3738494 . PMID   23950709.
  41. Lang Kuhs KA, Kuniholm MH, Pfeiffer RM, Chen S, Desai S, Edlin BR, et al. (October 2015). Ashkar AA (ed.). "Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes". PLOS ONE. 10 (10): e0138827. Bibcode:2015PLoSO..1038827L. doi: 10.1371/journal.pone.0138827 . PMC   4592222 . PMID   26431156.
  42. Bibert S, Wojtowicz A, Taffé P, Manuel O, Bernasconi E, Furrer H, et al. (August 2014). "The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients" (PDF). AIDS. 28 (13): 1885–9. doi:10.1097/QAD.0000000000000379. PMID   25259701. S2CID   24836153.
  43. Manuel O, Wójtowicz A, Bibert S, Mueller NJ, van Delden C, Hirsch HH, et al. (March 2015). "Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation". The Journal of Infectious Diseases. 211 (6): 906–14. doi: 10.1093/infdis/jiu557 . PMID   25301956.
  44. Annibali O, Piccioni L, Tomarchio V, Circhetta E, Sarlo C, Franceschini L, et al. (July 2018). Ciccozzi M (ed.). "Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients". PLOS ONE. 13 (7): e0200221. Bibcode:2018PLoSO..1300221A. doi: 10.1371/journal.pone.0200221 . PMC   6056038 . PMID   30036376.
  45. Hamming OJ, Terczyńska-Dyla E, Vieyres G, Dijkman R, Jørgensen SE, Akhtar H, et al. (November 2013). "Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses". The EMBO Journal. 32 (23): 3055–65. doi:10.1038/emboj.2013.232. PMC   3844954 . PMID   24169568.
  46. 1 2 3 Obajemu AA, Rao N, Dilley KA, Vargas JM, Sheikh F, Donnelly RP, et al. (December 2017). "IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling". Journal of Immunology. 199 (11): 3808–3820. doi:10.4049/jimmunol.1700807. PMC   5698113 . PMID   29070670.
  47. 1 2 3 Onabajo OO, Muchmore B, Prokunina-Olsson L (October 2019). "The IFN-λ4 Conundrum: When a Good Interferon Goes Bad". Journal of Interferon & Cytokine Research. 39 (10): 636–641. doi:10.1089/jir.2019.0044. PMC   6767864 . PMID   31241411.
  48. Schoggins JW, Rice CM (December 2011). "Interferon-stimulated genes and their antiviral effector functions". Current Opinion in Virology. 1 (6): 519–25. doi:10.1016/j.coviro.2011.10.008. PMC   3274382 . PMID   22328912.
  49. Wong MT, Chen SS (January 2016). "Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection". Cellular & Molecular Immunology. 13 (1): 11–35. doi:10.1038/cmi.2014.127. PMC   4712384 . PMID   25544499.
  50. Sung PS, Hong SH, Chung JH, Kim S, Park SH, Kim HM, et al. (June 2017). "IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection". Scientific Reports. 7 (1): 3821. Bibcode:2017NatSR...7.3821S. doi:10.1038/s41598-017-04186-7. PMC   5476576 . PMID   28630501.
  51. Fan W, Xie S, Zhao X, Li N, Chang C, Li L, et al. (September 2016). "IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18". The Journal of General Virology. 97 (9): 2210–2220. doi: 10.1099/jgv.0.000522 . PMID   27302182. S2CID   36253033.
  52. Waldenström J, Hellstrand K, Westin J, Nilsson S, Christensen P, Färkkilä M, et al. (2021). "Presence of Interferon-λ 4, Male Gender, Absent/Mild Steatosis and Low Viral Load Augment Antibody Levels to Hepatitis C Virus". Scandinavian Journal of Gastroenterology. 56 (7): 849–854. doi: 10.1080/00365521.2021.1922750 . hdl: 11250/2992668 . PMID   34078234.
  53. O'Brien TR, Kottilil S, Pfeiffer RM (December 2017). "IFNL4 Genotype Is Associated With Virologic Relapse After 8-Week Treatment With Sofosbuvir, Velpatasvir, and Voxilaprevir". Gastroenterology. 153 (6): 1694–1695. doi: 10.1053/j.gastro.2017.06.069 . PMC   7390973 . PMID   29107709.
  54. Lazear HM, Daniels BP, Pinto AK, Huang AC, Vick SC, Doyle SE, et al. (April 2015). "Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier". Science Translational Medicine. 7 (284): 284ra59. doi:10.1126/scitranslmed.aaa4304. PMC   4435724 . PMID   25904743.
  55. Crotta S, Davidson S, Mahlakoiv T, Desmet CJ, Buckwalter MR, Albert ML, et al. (November 2013). Kawaoka Y (ed.). "Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia". PLOS Pathogens. 9 (11): e1003773. doi: 10.1371/journal.ppat.1003773 . PMC   3836735 . PMID   24278020.
  56. Klinkhammer J, Schnepf D, Ye L, Schwaderlapp M, Gad HH, Hartmann R, et al. (April 2018). "IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission". eLife. 7: e33354. doi: 10.7554/eLife.33354 . PMC   5953542 . PMID   29651984.
  57. Galani IE, Triantafyllia V, Eleminiadou EE, Koltsida O, Stavropoulos A, Manioudaki M, et al. (May 2017). "Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness". Immunity. 46 (5): 875–890.e6. doi: 10.1016/j.immuni.2017.04.025 . PMID   28514692.
  58. Nice TJ, Baldridge MT, McCune BT, Norman JM, Lazear HM, Artyomov M, et al. (January 2015). "Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity". Science. 347 (6219): 269–73. Bibcode:2015Sci...347..269N. doi:10.1126/science.1258100. PMC   4398891 . PMID   25431489.
  59. Hernández PP, Mahlakoiv T, Yang I, Schwierzeck V, Nguyen N, Guendel F, et al. (July 2015). "Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection". Nature Immunology. 16 (7): 698–707. doi:10.1038/ni.3180. PMC   4589158 . PMID   26006013.

Further reading

This article incorporates text from the United States National Library of Medicine  (), which is in the public domain.