Immune Escape via a Transient Gene Expression Program Enables Productive Replication of a Latent Pathogen

Abstract

SUMMARY How type I/II interferons prevent periodic reemergence of latent pathogens in tissues of diverse cell-types remains unknown. Using homogenous neuron cultures latently-infected with herpes simplex virus-1, we show that extrinsic type I or II interferon act directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called Phase I. Surprisingly, interferons suppressed reactivation only during a limited period early in Phase I preceding productive virus growth. Sensitivity to type II interferon was selectively lost if viral ICP0, which normally accumulates later in Phase I, was expressed before reactivation. Thus, interferons suppress reactivation by preventing initial expression of latent genomes but are ineffective once Phase I viral proteins accumulate, limiting interferon action. This demonstrates that inducible reactivation from latency is only transiently sensitive to interferon. Moreover, it illustrates how latent pathogens escape host immune control to periodically replicate by rapidly deploying an interferon-resistant state.

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

“…Pretreatment with a mixture of IFN-α and IFN-γ in combination with ACV is required to establish latency in neurons from the SCG of post-natal mice again perhaps reflecting differences in host species or neuronal maturity [23]. In other experiments we found that IFN-γ was not effective in controlling HSV-1 in our human neuronal cultures and was toxic to the neurons in combination with IFN-α [25]. …”

Topoisomerase 2β-dependent nuclear DNA damage shapes extracellular growth factor responses through AKT phosphorylation dynamics to control virus latency

“…Sympathetic neurons from dissociated superior cervical ganglia (SCG) neurons from E21 rat embryos can be cultured as a pure population of cells that depend upon the trophic factor NGF (Glebova and Ginty, 2005). To determine whether genotoxic stress can affect HSV-1 latency in SCG neurons, we utilized a primary neuronal culture model system for establishing HSV-1 latency in vitro and employed a wildtype HSV-1 strain expressing the enhanced Green Fluorescent Protein (GFP) fused to the Us11 true-late (g2) protein (GFP-Us11) that can be detected during reactivation in living neurons (Benboudjema et al, 2003;Camarena et al, 2010;Kobayashi et al, 2012a;Linderman et al, 2017;Pourchet et al, 2017) (Figure 1A). Treatment of HSV-1 latently-infected neurons with either Bleomycin (DSB inducer, radiomimetic) or Etoposide (DSB inducer, TOP2 inhibitor) caused viral reactivation (productive viral replication leading to GFP-positive wells) at levels comparable to treatment with LY294002 (PI 3-kinase inhibitor, positive control).…”

Shared ancestry of herpes simplex virus 1 strain Patton with recent clinical isolates from Asia and with strain KOS63

“…Patton has been used extensively in laboratory studies, including, but not limited to, early studies of mRNA splicing (Watson et al, 1981), identification of lytic cycle proteins involved in viral DNA replication (Graham et al, 1978), drug resistance (Furman et al, 1981), pathogenesis (Bonneau and Jennings, 1989; Mohr et al, 2001; Morahan et al, 1981; Ward et al, 2003), and oncolytic virus development (Pourchet et al, 2016; Taneja et al, 2001). The GFP-US11 recombinant has served as a versatile reporter simplifying the development of in vitro latency models (Camarena et al, 2010; Kuhn et al, 2012; Pourchet et al, 2017; Roehm et al, 2011), and has been used in more detailed studies of reactivation (Kim et al, 2012), maintenance of latency by nerve growth factor signaling (Camarena et al, 2010; Kobayashi et al, 2012), and the suppression of reactivation by interferon (Linderman et al, 2017). Understanding the genomic structure of Patton and its evolutionary relationship to other strains and clinical isolates is therefore important.…”