Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Abstract

The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

Antiviral Effects of Curcumin on Adenovirus Replication

“…Treatment with curcumin dramatically lowered the levels of E1A produced from this virus and, as a result, HAdV replication was not rescued. However, since the HCMV immediate early enhancer/promoter is the first promoter activated during native HCMV infection and drives expression of proteins crucial for efficient initiation of the HCMV lifecycle [ 42 ], our observation suggests that curcumin could also be an effective treatment for HCMV.…”

Regulation of the MIE Locus During HCMV Latency and Reactivation

“…The MIE enhancer is further characterized into the proximal enhancer (between position −299 to −39) and the distal enhancer (between position −579 to −300) [72][73][74]. Most transcription factors that bind to and regulate the MIE locus bind within the enhancer region, although some bind the unique (position −750 to −500) or modulator regions (position −1140 to −750) [75]. The enhancer regulates transcription, in part, through small cis-acting repeat sequences of 18-bp, 19-bp, and 21-bp, to which trans-acting factors bind [74,76,77].…”

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review

“…After pp71 entry into the nucleus, it combines with death domain-associated protein (Daxx), which binds to histone deacetylases (HDACs) to repress transcription, thereby causing the degradation of Daxx and inducing the activation of the IE genes (Saffert and Kalejta, 2006). Then, as replication begins, the proteins in IE (pIE) can act as activators to promote the expression of early and late genes via their interaction with cytokines (Adamson and Nevels, 2020). Early proteins are mainly transcription factors and polymerases involved in viral DNA replication, transcription, and protein synthesis, whereas late proteins are mainly structural proteins synthesized after viral DNA replication (Gruffat et al, 2016).…”