Viral gene products actively promote latent infection by epigenetic silencing mechanisms
Introduction
Many viruses undergo an acute infection in the host organism and then are cleared by the ensuing host immune response. However, other viruses establish a persistent infection by either establishing a latent infection, in which the virus is quiescent and no infectious virus can be detected, or a chronic infection, in which infectious virus is continually produced. The herpesviruses are good examples of viruses that establish a latent infection. Herpes simplex virus (HSV) undergoes an acute lytic infection in the mucosal epithelium and spreads to establish a latent infection in sensory neurons. Historically, there was debate about whether HSV latent infection was truly quiescent or ‘static’ versus slowly replicating or ‘dynamic’ [1]. The studies of Jack Stevens establishing a murine model of latent HSV infection showed that the virus is quiescent during latent infection in this murine infection model [2]. There is little to no oral shedding of HSV-1 from humans, but Corey et al. have detected frequent low level HSV-2 genital shedding in certain study populations [3], and they have argued for a chronic infection. However, their modeling studies argue that only a low fraction of neurons are reactivating at any time in these individuals [4], so the bulk of HSV-2 latent infection is relatively quiescent. In murine models of HSV-1 latent infection, there is low level expression of lytic transcripts [5, 6], and this is likely due to abortive or nonproductive reactivation events [5, 7].
A second important question concerning viral latent infection has been whether it is a default pathway due simply to viral infection of non-permissive cells or whether the virus plays an active role in the establishment of latent infection. Originally, viruses were thought to undergo a latent infection when they enter a non-permissive cell and go quiescent as a default pathway. Recent studies have shown that several viral gene products can actively promote latent infection by epigenetic silencing of their respective viral DNA genomes, by preventing cell death, or by tethering of the viral genome to cellular chromosomes in dividing cells. In this mini-review, we will focus on those gene products that have been shown to promote epigenetic silencing and thereby facilitate latent infection.
Section snippets
Herpes simplex virus (HSV)
HSV undergoes a lytic infection in epithelial cells and fibroblasts and spreads to establish a latent infection in sensory neurons. In epithelial cells, HSV expresses its lytic gene products in a cascade of immediate-early (IE), early (E), and late (L) gene products. The HSV virion protein 16 (VP16) forms a complex in the infected cell nucleus with the cellular Oct-1 and host cell factor 1 (HCF-1) proteins in which Oct-1 binds to IE gene promoters and HCF-1 recruits epigenetic factors to remove
Human cytomegalovirus (HCMV)
HCMV undergoes a productive infection in primary fibroblasts, but establishes a latent infection when it infects hematopoetic progenitor stem cells [26]. In the latter cells, lytic genes are repressed and only a few latency-associated transcripts are expressed. Like other herpesviruses, the HCMV genome is maintained as a chromatinized episome in latency. Similar to HSV-1, HCMV genomes are not silenced by DNA methylation [27]. In CD34+ cells, the major immediate-early promoter (MIEP) is
Epstein–Barr virus (EBV)
EBV undergoes a productive infection in oral epithelial cells and then spreads to infect B lymphocytes, which results in a series of latency states characterized by different patterns of EBV gene expression. The initial infection of resting B lymphocytes results in a state (latency III) with expression of a number of latent gene products including Epstein–Barr nuclear antigen (EBNA) -1, -2, 3A-C, EBNA-LP (EBNA leader protein), latent membrane protein (LMP) -1, -2A, -2B, and the EBER transcripts
Human herpesvirus 8 or Kaposi’s sarcoma-associated herpesvirus (KSHV)
KSHV is primarily associated with B cells but is also associated with endothelial cell tumor cells and can enter a broad variety of cells [40]. The default pathway of infection is a latent infection, but spontaneous reactivation is observed in a fraction of the cells. KSHV latent infection is associated with Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Several viral gene products are known to promote epigenetic silencing of the viral genome and
Human immunodeficiency virus
Human immunodeficiency virus (HIV) uses its reverse transcriptase enzyme to copy its genomic RNA into cDNA and then double-stranded DNA within subviral particles in the cytoplasm [50]. The DNA is then transported in this preinitiation complex into the cell nucleus, where the virus-encoded integrase mediates the integration of the viral DNA into cellular chromosomes to give a proviral genome. In activated T lymphocytes the provirus is transcribed by the cellular RNA polymerase II to give viral
Summary and perspectives
It has become clear that viruses that establish a latent infection and persist in the host organism can play an active role in establishment of that infection by encoding their own gene products that modulate the viral chromatin to epigenetically silence their genome through a number of common and distinct pathways. In particular, the herpesviruses encode gene products, both proteins and RNAs, that directly or indirectly promote epigenetic silencing and latent infection. This knowledge has two
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
•• of outstanding interest
Acknowledgments
We thank Patrick T. Waters for assistance in preparation of the manuscript. Research in the authors’ laboratory on HSV latency is supported by NIH grantP01 AI098681.
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