HIV-1 TAR RNA Has an Intrinsic Ability to Activate Interferon-Inducible Enzymes

Maitra, Ratan K.; McMillan, Nigel A.J.; Desai, Shailesh Y.; McSwiggen, James A.; Hovanessian, Ara G.; Sen, Ganes C.; Williams, Bryan R.G.; Silverman, Robert H.

doi:10.1006/viro.1994.1601

Cited by 141 publications

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“…Indeed, RNases are typically present in very low amount in cells associated with a specific inhibitor or are present in an inactive latent form requiring the presence of a specific activator. This is the case for RNase L, whose activation requires the presence of oligoadenylates synthesized by 2Ј-5Ј oligoadenylate synthetase in response to replicating dsRNA forms of viruses such as EMCV (12,50,51). It is conceivable that such a mechanism could be involved in a local activation of ISG20 preventing cell toxicity.…”

Section: Discussionmentioning

confidence: 99%

ISG20, a New Interferon-induced RNase Specific for Single-stranded RNA, Defines an Alternative Antiviral Pathway against RNA Genomic Viruses

Espert

Degols

Gongora

et al. 2003

Journal of Biological Chemistry

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197

196

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Interferons (IFNs) encode a family of secreted proteins that provide the front-line defense against viral infections. Their diverse biological actions are thought to be mediated by the products of specific but usually overlapping sets of cellular genes induced in the target cells. We have recently isolated a new human IFN-induced gene that we have termed ISG20, which codes for a 3 to 5 exonuclease with specificity for single-stranded RNA and, to a lesser extent, for DNA. In this report, we demonstrate that ISG20 is involved in the antiviral functions of IFN. In the absence of IFN treatment, ISG20-overexpressing HeLa cells showed resistance to infections by vesicular stomatitis virus (VSV), influenza virus, and encephalomyocarditis virus (three RNA genomic viruses) but not to the DNA genomic adenovirus. ISG20 specifically interfered with VSV mRNA synthesis and protein production while leaving the expression of cellular control genes unaffected. No antiviral effect was observed in cells overexpressing a mutated ISG20 protein defective in exonuclease activity, demonstrating that the antiviral effects were due to the exonuclease activity of ISG20. In addition, the inactive mutant ISG20 protein, which is able to inhibit ISG20 exonuclease activity in vitro, significantly reduced the ability of IFN to block VSV development. Taken together, these data suggested that the antiviral activity of IFN against VSV is partly mediated by ISG20. We thus show that, besides RNase L, ISG20 has an antiviral activity, supporting the idea that it might represent a novel antiviral pathway in the mechanism of IFN action. Interferons (IFNs)1 are a family of multifunctional secreted proteins characterized by their abilities to interfere with virus infection and replication (1, 2). IFNs can indirectly inhibit viral production by reducing the growth of target cells and by stimulating their susceptibility to apoptotic processes (3, 4) or by promoting the recognition and the cytotoxic killing of infected cells by the immune system (5, 6). IFNs also act directly at various steps of the viral multiplication cycle through the products of specific but usually overlapping sets of cellular genes induced in the target cells and involved in RNA and protein metabolism and signaling as well (7,8). Until now, three IFNregulated pathways have been considered to be involved in these processes: the double-stranded RNA-dependent protein kinase R (PKR) (9 -11), the 2-5A/RNase L system (12, 13), and the Mx proteins (14 -16). PKR is a serine/threonine kinase that, after binding to dsRNA, phosphorylates the protein synthesis initiation factor eIF2 and the inhibitor of nuclear factor B (IB), resulting in the inhibition of protein synthesis and specific transcription regulation (reviewed in . RNase L is a dormant cytosolic endoribonuclease that is activated by short oligoadenylates produced by the 2Ј-5Ј oligoadenylate synthetase after viral infection or IFN exposure (reviewed in Refs. 2 and 13). Degradation of viral RNAs and cleavage of cellular 18 S and 28 S rRNA...

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Section: Discussionmentioning

confidence: 99%

ISG20, a New Interferon-induced RNase Specific for Single-stranded RNA, Defines an Alternative Antiviral Pathway against RNA Genomic Viruses

Espert

Degols

Gongora

et al. 2003

Journal of Biological Chemistry

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197

196

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“…For example, HIV-1 (Martinand et al, 1999) and EMCV (Martinand et al, 1998) apparently downregulate RNase L activity by inducing the expression of the cellular RNase L inhibitor (RLI), which antagonizes 2959-oligoadenylate binding to RNase L and hence prevents its activation. With regards to HIV, potentially the TAR sequence structural element could also bind and activate OAS and PKR, but this is prevented by the virus Tat protein binding the TAR element (Maitra et al, 1994).…”

Section: General Considerations Of How Viruses Evade the Ifn Responsementioning

confidence: 99%

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Randall

Goodbourn

2008

Journal of General Virology

1,387

1,420

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The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer. Biology of the interferon systemThe interferons (IFNs) are a group of secreted cytokines that elicit distinct antiviral effects. They are grouped into three classes called type I, II and III IFNs, according to their amino acid sequence. Type I IFNs (discovered in 1957;Isaacs & Lindenmann, 1957) comprise a large group of molecules; mammals have multiple distinct IFN-a genes (13 in man), one to three IFN-b genes (one in man) and other genes, such as IFN-v, -e, -t, -d and -k. The IFN-a and -b genes are induced directly in response to viral infection, whereas IFN-v, -e, -d and -k play less well-defined roles, such as regulators of maternal recognition in pregnancy. Thus, rather than use the term 'type I IFN', we will use IFN-a/b when referring to the virally induced cytokines. Although the multigenic nature of IFN-a has been known for over 20 years, the significance of this is still debatedi.e. whether these genes are expressed differentially in distinct cell types, whether they are inducible by different types of viruses or whether they are functionally specialized (Brideau-Andersen et al., 2007). For the rest of this review, we will not distinguish between IFN-a subtypes. Type III IFNs have been described more recently and comprise IFNl1, -l2 and -l3, also referred to as IL-2...

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“…Moreover, complexes between EMCV dsRNA and 2-5A-synthetase that produce 2-5A from ATP have been isolated from virus-infected cells [70]. Several viral RNAs can activate 2-5A-synthetase including adenoviral VAI RNA [71], TAR RNA of human immunodeficiency virus type 1 (HIV-1) [72], REX-RE RNA of Human T-cell Leukemia virus type I (HTLV-1) [73], and EBER-1 RNA of Epstein-Barr virus [74]. Cleavage of viral mRNA by RNase L in intact cells has been demonstrated during treatment of vesicular stomatitis virus-infected cells with 2-5A [75], HIV-1 and EMCV infection [44,45].…”

Section: Iii) Biological Activities Of Rnase L 1) Antiviral Activitymentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFN). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. KeywordsInterferon; RNase L; RNA expression; apoptosis; prostate; virus; cancer I) IntroductionThe endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway regulated by interferons (IFN) [1] (Figure 1). The 2-5A system is one of the two antiviral pathways induced by IFN and activated by double stranded RNA (dsRNA), the other is mediated by the dsRNA dependent protein kinase (PKR) [2]. RNase L is a very unusual nuclease. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A ( Figure 1). 2-5A itself is very unusual, consisting of a series of 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds in contrast to the 3′-5′ linkages found in RNA and DNA. The initial and essential observation was made by Ian Kerr's group in 1974 reporting an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [3]. Peter Lengyel's group observed increased nuclease activity in extracts of interferon treated cells incubated with dsRNA [4,5]. The identification by Ian Kerr's group of the activators of this nuclease, 2-5A [6] and of the enzyme responsible for their synthesis, the 2-5A-synthetase [7][8][9], led to the discovery of the 2-5A pathway. Clemens and Williams directly demonstrated a nuclease, now recognized as RNase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 2). The N-terminal domain could be considered as the regulatory domain of RNase L. It is composed of eight complete and one partial ankyrin motifs (R1-R9). Two wal...

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HIV-1 TAR RNA Has an Intrinsic Ability to Activate Interferon-Inducible Enzymes

Cited by 141 publications

References 0 publications

ISG20, a New Interferon-induced RNase Specific for Single-stranded RNA, Defines an Alternative Antiviral Pathway against RNA Genomic Viruses

ISG20, a New Interferon-induced RNase Specific for Single-stranded RNA, Defines an Alternative Antiviral Pathway against RNA Genomic Viruses

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Diverse functions of RNase L and implications in pathology

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