Abstract

The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. Both proteins have long been recognized as promiscuous transcriptional regulators. More recently, a critical role of the IE1 and IE2 proteins in counteracting non-adaptive host cell defense mechanisms has been revealed. In this review we will briefly summarize the available literature on IE1- and IE2-dependent mechanisms contributing to CMV evasion from intrinsic and innate immune responses.

Highlights

  • The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency

  • (Figure 1), the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. They share 85 amino-terminal amino acids corresponding to major IE exons 2 and 3 but have distinct carboxy-terminal parts encoded by exon 4 (IE1) or exon 5 (IE2) (Figure 1)

  • The first mechanism depends on binding of IFN-activatable STAT2 to the carboxy-terminal IE1 domain resulting in inhibition of ISGF3-mediated anti-viral gene induction

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Summary

Structure and Importance of the Major IE Gene

The predominant major IE protein species, which are the subject of this review, are highlighted in blue. It is uncertain whether the IE1 isoforms shown in gray are present in CMVinfected cells [4]. Polyadenylation and promoter usage this viral genomic region produces multiple mRNAs (reviewed in [3]). (Figure 1), the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. They share 85 amino-terminal amino acids corresponding to major IE exons 2 and 3 but have distinct carboxy-terminal parts encoded by exon 4 (IE1) or exon 5 (IE2) (Figure 1). The absence of IE1 results in severely attenuated viral replication under low MOI conditions [10,11]

Functional Activities of the IE1 and IE2 Proteins
IE1 and IE2 in Innate and Intrinsic Immunity
Apoptosis Pathways in Antiviral Host Defense
Role of IE1 and IE2 in Apoptosis Inhibition
Association of Parental Viral Genomes and IE Proteins with ND10
IE1 as Antagonist of ND10-Related Intrinsic Defenses
Cytokine-Based Innate Immunity Against Viral Infection
IE2-Mediated Inhibition of Cytokine Induction
IE1-Mediated Inhibition of Jak-STAT signaling
Conclusions
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