Immune responses against HSV-1 and HSV-2 are complex and involve a delicate interplay between innate signaling pathways and adaptive immune responses. The innate response to HSV involves the induction of type I IFN, whose role in protection against disease is well characterized in vitro and in vivo. Cell types such as NK cells and pDCs contribute to innate anti-HSV responses in vivo. Finally, the adaptive response includes both humoral and cellular components that play important roles in antiviral control and latency. This review summarizes the innate and adaptive effectors that contribute to susceptibility, immune control and pathogenesis of HSV, and highlights the delicate interplay between these two important arms of immunity.

SummaryThe type I interferon (IFN) system mediates a wide variety of antiviral effects and represents an important first barrier to virus infection. Consequently, viruses have developed an impressive diversity of tactics to circumvent IFN responses. Evasion strategies can involve preventing initial virus detection, via the disruption of the Toll-like receptors or the retinoic acid inducible gene I (RIG-I) -like receptors, or by avoiding the initial production of the ligands recognized by these receptors. An alternative approach is to preclude IFN production by disarming or degrading the transcription factors involved in the expression of IFN, such as interferon regulatory factor 3 (IRF3)/IRF7, nuclear factor-jB (NF-jB), or ATF-2/ c-jun, or by inducing a general block on host cell transcription. Viruses also oppose IFN signalling, both by disturbing the type I IFN receptor and by impeding JAK/STAT signal transduction upon IFN receptor engagement. In addition, the global expression of IFN-stimulated genes (ISGs) can be obstructed via interference with epigenetic signalling, and specific ISGs can also be selectively targeted for inhibition. Finally, some viruses disrupt IFN responses by co-opting negative regulatory systems, whereas others use antiviral mechanisms to their own advantage. Here, we review recent developments in this field.

We previously found that enveloped virus binding and penetration are necessary to initiate an interferonindependent, IRF3-mediated antiviral response. To investigate whether membrane perturbations that accompany membrane fusion-dependent enveloped-virus entry are necessary and sufficient for antiviral-state induction, we utilized a reovirus fusion-associated small transmembrane (FAST) protein. Membrane disturbances during FAST protein-mediated fusion, in the absence of additional innate immune response triggers, are sufficient to elicit interferon-stimulated gene induction and establishment of an antiviral state. Using sensors of membrane disruption to activate an IRF3-dependent, interferon-independent antiviral state may provide cells with a rapid, broad-spectrum innate immune response to enveloped-virus infections.

The immediate-early protein ICP0 from herpes simplex virus 1 (HSV-1) plays pleiotropic roles in promoting viral lytic replication and reactivation from latency. Most of the known actions of ICP0 occur in the nucleus and are thought to involve the E3 ubiquitin ligase activity of its RING finger domain, which targets proteins for degradation via the proteasome. Although ICP0 translocates to the cytoplasm as the infection progresses, little is known about its activities in this location. Here, we show that cytoplasmic ICP0 has two distinct functions. In primary cell cultures and in an intravaginal mouse model, cytoplasmic ICP0 promotes viral replication in the absence of an intact RING finger domain. Additionally, ICP0 blocks the activation of interferon regulatory factor 3 (IRF3), a key transcription factor of the innate antiviral response, in a mechanism that requires the RING finger domain but not the proteasome. To our knowledge, this is the first observation of a proteasome-independent function of the RING finger domain of ICP0. Collectively, these results underscore the importance of cytoplasm-localized ICP0 and the diverse nature of its activities. IMPORTANCEDespite ICP0 being a well-studied viral protein, the significance of its cytoplasmic localization has been largely overlooked. This is, in part, because common experimental manipulations result in the restriction of ICP0 to the nucleus. By overcoming this constraint, we both further characterize the ability of cytoplasmic ICP0 to inhibit antiviral signaling and show that ICP0 at this site has unexpected activities in promoting viral replication. This demonstrates the importance of considering location when analyzing protein function and adds a new perspective to our understanding of this multifaceted protein.

It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the transGolgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. W ith worldwide seroprevalence rates reaching 60 to 90% (1), herpes simplex virus 1 (HSV-1) is a tremendously successful human pathogen. HSV-1 particles consist of a double-stranded DNA genome encased by an icosahedral capsid, surrounded by a proteinaceous layer known as the tegument, which is in turn enclosed by an envelope of host-derived lipids (2). During the lytic replication cycle, viral glycoprotein-mediated fusion of the envelope with the host cell plasma membrane releases the capsid and tegument proteins into the cytosol (3). HSV capsids are then transported to the nucleus along microtubules via molecular motor proteins (4). The release of the genome into the nucleus is followed by viral gene expression in a sequential manner, beginning with the immediate-early (IE) genes and then progressing to the early (E) and late (L) classes, resulting in viral genomic DNA replication and packaging into capsids.Although subsequent steps have been controversial, it is n...