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Review
. 2000 Dec;64(4):709-24.
doi: 10.1128/MMBR.64.4.709-724.2000.

Cytopathogenesis and inhibition of host gene expression by RNA viruses

D S Lyles  1
Affiliations
Review

Cytopathogenesis and inhibition of host gene expression by RNA viruses

D S Lyles. Microbiol Mol Biol Rev. 2000 Dec.

Abstract

Many viruses interfere with host cell function in ways that are harmful or pathological. This often results in changes in cell morphology referred to as cytopathic effects. However, pathogenesis of virus infections also involves inhibition of host cell gene expression. Thus the term "cytopathogenesis," or pathogenesis at the cellular level, is meant to be broader than the term "cytopathic effects" and includes other cellular changes that contribute to viral pathogenesis in addition to those changes that are visible at the microscopic level. The goal of this review is to place recent work on the inhibition of host gene expression by RNA viruses in the context of the pathogenesis of virus infections. Three different RNA virus families, picornaviruses, influenza viruses, and rhabdoviruses, are used to illustrate common principles involved in cytopathogenesis. These examples were chosen because viral gene products responsible for inhibiting host gene expression have been identified, as have some of the molecular targets of the host. The argument is made that the role of the virus-induced inhibition of host gene expression is to inhibit the host antiviral response, such as the response to double-stranded RNA. Viral cytopathogenesis is presented as a balance between the host antiviral response and the ability of viruses to inhibit that response through the overall inhibition of host gene expression. This balance is a major determinant of viral tissue tropism in infections of intact animals.

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Figures

FIG. 1
FIG. 1
Formation of preinitiation complex for RNAPII. Enhancer-binding proteins such as Oct-1 and CREB interact with TAFII subunits of TFIID. The TBP subunit of TFIID binds the TATA box DNA element and recruits the remaining basal transcription factors, TFIIA, TFIIB, TFIIE, TFIIF, TFIIH, and TFIIJ, as well as RNAPII, to the promoter initiation site (Inr). Proteins which are targets for inhibition by picornavirus 3C protease and VSV M protein are indicated.
FIG. 2
FIG. 2
Processing and transport of cellular mRNAs. Step 1 (clockwise from right): CPSF binds to the AAUAAA sequence of the mRNA precursor; other proteins involved in cleavage and oligoadenylation are cleavage factors 1 and 2 (CF1, CF2), cleavage stimulation factor (CstF), and poly(A) polymerase (PAP). Step 2: Oligonucleotide A at the 3′ end of mRNA precursor is bound by PABII, which stimulates polyadenylation by PAP. Step 3: The mRNA precursor is spliced by U1, U2, U3, U4, U5, and U6 snRNPs. The processed mRNA is transported to the cytoplasm by export receptors that require Ran-GTP. Hydrolysis of GTP by Ran is stimulated by RanGAP1 in the cytoplasm, which causes the release of mRNA. Exchange of the GDP of Ran for GTP is stimulated by RCC1 in the nucleus. The sites of inhibition by influenza virus NS1 protein are indicated. Inhibition by VSV M protein is shown at the RCC1 step because it resembles inhibition by a ts mutation in RCC1, but the actual target could be some other step in the Ran-GTP/Ran-GDP cycle.
FIG. 3
FIG. 3
Formation of the translation initiation complex. mRNA is bound by the eIF4F complex, which consists of eIF4A, eIF4B, eIF4E, and eIF4G. The 5′ end of mRNA is bound by the cap-binding subunit, eIF4E. This requires phosphorylation of eIF4E by the protein kinase MNK1. The 3′ end of mRNA is bound by the cytoplasmic PAB. eIF4G binds eIF4A, eIF4B, eIF4E, PAB, and MNK1 to the other elements of the initiation complex through eIF3. eIF2 binds Met-tRNAF and GTP and then binds the 40S ribosomal subunit upon hydrolysis of GTP. Proteins which are targets for inhibition by picornavirus 2A proteases, influenza virus, and PKR activated by VSV are indicated.
FIG. 4
FIG. 4
Models for the balance between virus-induced inhibition of host gene expression and the host antiviral response. The virus-induced inhibition of host gene expression includes the effects of such proteins as poliovirus 3C and 2A proteases, influenza virus NS1 protein, and VSV M protein. The production of dsRNA is meant to be the prototype for a viral gene product that provokes an antiviral response in host cells. Three different host responses are shown. The inhibition of total host mRNA synthesis represents the result of all of the viral inhibitory mechanisms, including inhibition of transcription, processing, and transport of mRNA. The synthesis of alpha/beta interferon (IFN) mRNA is shown as a balance between stimulation by dsRNA and inhibition that parallels the overall inhibition of host mRNA synthesis. The progression of apoptosis is shown as a process that is promoted both by viral inhibitory proteins and by the host response. For the sake of argument, the apoptotic response to virus-induced inhibition of host gene expression is assumed to occur more slowly than the apoptotic response to dsRNA and interferon and the viral proteins are assumed to initially inhibit the response to dsRNA. (A) Typical pattern of virus-host interaction for RNA viruses. (B) Pattern of virus-host interaction for cells that are less capable of responding to viral dsRNA, for viruses that produce less dsRNA, or for viruses that are more effective in the inhibition of host gene expression. (C) Pattern of virus-host interaction for viral mutants that are defective in the inhibition of host gene expression or for cells that are hyperresponsive to dsRNA. (D) Pattern of virus-host interaction for noncytopathic viruses.
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