Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in Promyelocytic Leukemia Nuclear Bodies.

Promyelocytic leukemia nuclear bodies (PML-NBs) possess an important intrinsic antiviral activity against alphaherpesvirus infection. PML is the structural backbone of NBs, comprising different isoforms. However, the contribution of each isoform to alphaherpesvirus restriction is not well understood. Here, we report the role of PML-NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in the context of increasing the expression level of endogenous sPML. Of four sPML isoforms cloned and examined, only isoforms sPML-II and -IIa, not sPML-I and -IVa, expressed in a sPML knockout cells inhibit PRV infection. Both the unique 7b region of sPML-II and the sumoylation-dependent normal formation of PML-NBs are required. 7b possesses a transcriptional repression activity and suppresses viral gene transcription during PRV infection with the cysteine residues 589 and 599 being critically involved. We conclude that sPML-NBs inhibit PRV infection partly by repressing viral gene transcription through the 7b region of sPML-II.IMPORTANCE PML-NBs are nuclear sites that mediate the antiviral restriction of alphaherpesvirus gene expression and replication. However, the contribution of each PML isoform to this activity of PML-NBs is not well characterized. Using PRV and its natural host swine cells as a system, we have discovered that the unique C terminus of sPML isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in repression of viral gene transcription. Our study not only confirms in swine cells that PML-NBs have an antiviral function but also presents a mechanism to suggest that PML-NBs inhibit viral infection in an isoform specific manner.

Fatal necrotic tracheitis by Aviadenovirus in captive Alagoas curassows (Pauxi mitu) extinct from the wild.

Extinct from nature, captive young Alagoas curassows (Pauxi mitu) were found agonizing or dead with respiratory disease. Intranuclear inclusion bodies were found in the epithelia of the trachea, associated with marked necrotic tracheitis. An Aviadenovirus was isolated in chicken eggs and characterized genetically with 99% identity to the fowl Aviadenovirus A, as based on the hexon protein gene. This is the first report of respiratory disease caused by Aviadenovirus in any cracid species in Brazil, recommending for stricter biosecurity in the conservation premises. RESEARCH HIGHLIGHTS Fatal tracheitis in curassows extinct from nature was associated with Aviadenovirus A. Seven-month-old Alagoas curassows (Aves: Cracidae) died with haemorrhagic tracheitis. Aviadenovirus A with 99% identity to fowl adenovirus 1 was detected in dead curassows. Fatal tracheitis by Aviadenovirus was described in Pauxi mitu (Aves: Cracidae).

In Vitro Replication of Chelonid Herpesvirus 5 in Organotypic Skin Cultures from Hawaiian Green Turtles (Chelonia mydas).

Fibropapillomatosis (FP) is a tumor disease of marine turtles associated with chelonid herpesvirus 5 (ChHV5), which has historically been refractory to growth in tissue culture. Here we show, for the first time, de novo formation of ChHV5-positive intranuclear inclusions in cultured green turtle cells, which is indicative of active lytic replication of the virus. The minimal requirements to achieve lytic replication in cultured cells included (i) either in vitro cultures of ChHV5-positive tumor biopsy specimens (plugs) or organotypic cultures (rafts) consisting of ChHV5-positive turtle fibroblasts in collagen rafts seeded with turtle keratinocytes and (ii) keratinocyte maturation induced by raising raft or biopsy cultures to the air-liquid interface. Virus growth was confirmed by detailed electron microscopic studies that revealed intranuclear sun-shaped capsid factories, tubules, various stages of capsid formation, nuclear export by budding into the perinuclear space, tegument formation, and envelopment to complete de novo virus production. Membrane synthesis was also observed as a sign of active viral replication. Interestingly, cytoplasmic particles became associated with keratin filaments, a feature not seen in conventional monolayer cell cultures, in which most studies of herpesvirus replication have been performed. Our findings draw a rich and realistic picture of ChHV5 replication in cells derived from its natural host and may be crucial not only to better understand ChHV5 circulation but also to eventually complete Koch's postulates for FP. Moreover, the principles described here may serve as a model for culture of other viruses that are resistant to replication in conventional cell culture.IMPORTANCE A major challenge in virology is the study of viruses that cannot be grown in the laboratory. One example is chelonid herpesvirus 5 (ChHV5), which is associated with fibropapillomatosis, a globally distributed, debilitating, and fatal tumor disease of endangered marine turtles. Pathological examination shows that ChHV5 is shed in skin. Here we show that ChHV5 will grow in vitro if we replicate the complex three-dimensional structure of turtle skin. Moreover, lytic virus growth requires a close interplay between fibroblasts and keratinocytes. Finally, the morphogenesis of herpesviral growth in three-dimensional cultures reveals a far richer, and likely more realistic, array of capsid morphologies than that encountered in traditional monolayer cell cultures. Our findings have applications to other viruses, including those of humans.

PML plays both inimical and beneficial roles in HSV-1 replication.

After entry into the nucleus, herpes simplex virus (HSV) DNA is coated with repressive proteins and becomes the site of assembly of nuclear domain 10 (ND10) bodies. These small (0.1-1 µM) nuclear structures contain both constant [e.g., promyelocytic leukemia protein (PML), Sp100, death-domain associated protein (Daxx), and so forth] and variable proteins, depending on the function of the cells or the stress to which they are exposed. The amounts of PML and the number of ND10 structures increase in cells exposed to IFN-ß. On initiation of HSV-1 gene expression, ICP0, a viral E3 ligase, degrades both PML and Sp100. The earlier report that IFN-ß is significantly more effective in blocking viral replication in murine PML(+/+) cells than in sibling PML(-/-) cells, reproduced here with human cells, suggests that PML acts as an effector of antiviral effects of IFN-ß. To define more precisely the function of PML in HSV-1 replication, we constructed a PML(-/-) human cell line. We report that in PML(-/-) cells, Sp100 degradation is delayed, possibly because colocalization and merger of ICP0 with nuclear bodies containing Sp100 and Daxx is ineffective, and that HSV-1 replicates equally well in parental HEp-2 and PML(-/-) cells infected at 5 pfu wild-type virus per cell, but poorly in PML(-/-) cells exposed to 0.1 pfu per cell. Finally, ICP0 accumulation is reduced in PML(-/-) infected at low, but not high, multiplicities of infection. In essence, the very mechanism that serves to degrade an antiviral IFN-ß effector is exploited by HSV-1 to establish an efficient replication domain in the nucleus.

BK virus-associated nephropathy with hydronephrosis in a patient with AIDS: a case report and literature review.

BK virus is ubiquitous worldwide, with infection usually occurring in early childhood. BK virus replicates prolifically under immunosuppressive conditions, causing inflammation along the genitourinary tract and progressing clinically to hemorrhagic cystitis, ureteral stenosis, and tubulointerstitial nephritis. Most BK virusassociated nephropathy occurs in renal allograft patients after kidney transplantation, although some case reports have described BK virus-associated nephropathy in the native kidney, particularly in patients with human immunodeficiency virus infection. Here we present the case of a 49-year-old male with acquired immunodeficiency syndrome (AIDS) and renal dysfunction with hydronephrosis. The renal biopsy showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates and intranuclear inclusions in the tubular epithelium, which are typical findings for BK virus-associated nephropathy. In addition, immunohistochemical staining revealed that the SV40 large T antigen exhibited a nuclear localization in tubular cells. To the best of our knowledge, this is the first case report of BK virus-associated nephropathy combined with hydronephrosis that was diagnosed by biopsy in a patient with AIDS.

Progressive multifocal leukoencephalopathy: Dot-shaped inclusions and virus-host interactions.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC (JC virus). The pathology of affected brain tissues demonstrates oligodendroglia-like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot-shaped inclusions). The dot-shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early-stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti-viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus-host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a focus on the intranuclear target of JC virus infection and host inflammatory reactions.

JC virus inclusions in progressive multifocal leukoencephalopathy: scaffolding promyelocytic leukemia nuclear bodies grow with cell cycle transition through an S-to-G2-like state in enlarging oligodendrocyte nuclei.

In progressive multifocal leukoencephalopathy, JC virus-infected oligodendroglia display 2 distinct patterns of intranuclear viral inclusions: full inclusions in which progeny virions are present throughout enlarged nuclei and dot-shaped inclusions in which virions are clustered in subnuclear domains termed "promyelocytic leukemia nuclear bodies" (PML-NBs). Promyelocytic leukemia nuclear bodies may serve a scaffolding role in viral progeny production. We analyzed the formation process of intranuclear viral inclusions by morphometry and assessed PML-NB alterations in the brains of 2 patients with progressive multifocal leukoencephalopathy. By immunohistochemistry, proliferating cell nuclear antigen was most frequently detected in smaller nuclei; cyclin A was detected in larger nuclei. This suggests an S-to-G2 cell cycle transition in infected cells associated with nuclear enlargement. Sizes of PML-NBs were variable, but they were usually either small speckles 200 to 400 nm in diameter or distinct spherical shells with a diameter of 1 µm or more. By confocal microscopy, JC virus capsid proteins were associated with both small and large PML-NBs, but disruption of large PML-NBs was observed by ground-state depletion fluorescence nanoscopy. Clusters of progeny virions were also detected by electron microscopy. Our data suggest that, in progressive multifocal leukoencephalopathy, JC virus produces progeny virions in enlarging oligodendrocyte nuclei in association with growing PML-NBs and with cell cycle transition through an S-to-G2-like state.

Human respiratory syncytial virus nucleoprotein and inclusion bodies antagonize the innate immune response mediated by MDA5 and MAVS.

Currently, the spatial distribution of human respiratory syncytial virus (hRSV) proteins and RNAs in infected cells is still under investigation, with many unanswered questions regarding the interaction of virus-induced structures and the innate immune system. Very few studies of hRSV have used subcellular imaging as a means to explore the changes in localization of retinoic-acid-inducible gene-I (RIG-I)-like receptors or the mitochondrial antiviral signaling (MAVS) protein, in response to the infection and formation of viral structures. In this investigation, we found that both RIG-I and melanoma differentiation-associated gene 5 (MDA5) colocalized with viral genomic RNA and the nucleoprotein (N) as early as 6 h postinfection (hpi). By 12 hpi, MDA5 and MAVS were observed within large viral inclusion bodies (IB). We used a proximity ligation assay (PLA) and determined that the N protein was in close proximity to MDA5 and MAVS in IBs throughout the course of the infection. Similar results were found with the transient coexpression of N and the phosphoprotein (P). Additionally, we demonstrated that the localization of MDA5 and MAVS in IBs inhibited the expression of interferon ß mRNA 27-fold following Newcastle disease virus infection. From these data, we concluded that the N likely interacts with MDA5, is in close proximity to MAVS, and localizes these molecules within IBs in order to attenuate the interferon response. To our knowledge, this is the first report of a specific function for hRSV IBs and of the hRSV N protein as a modulator of the innate immune response.

The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1.

Herpes simplex virus type 1 (HSV-1) is a common human pathogen causing cold sores and even more serious diseases. It can establish a latent stage in sensory ganglia after primary epithelial infections, and reactivate in response to stress or sunlight. Previous studies have demonstrated that viral immediate-early protein ICP0 plays a key role in regulating the balance between lytic and latent infection. Recently, It has been determined that promyelocytic leukemia (PML) nuclear bodies (NBs), small nuclear sub-structures, contribute to the repression of HSV-1 infection in the absence of functional ICP0. In this review, we discuss the fundamentals of the interaction between ICP0 and PML NBs, suggesting a potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1.

Disruption of PML nuclear bodies is mediated by ORF61 SUMO-interacting motifs and required for varicella-zoster virus pathogenesis in skin.

Promyelocytic leukemia protein (PML) has antiviral functions and many viruses encode gene products that disrupt PML nuclear bodies (PML NBs). However, evidence of the relevance of PML NB modification for viral pathogenesis is limited and little is known about viral gene functions required for PML NB disruption in infected cells in vivo. Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes cutaneous lesions during primary and recurrent infection. Here we show that VZV disrupts PML NBs in infected cells in human skin xenografts in SCID mice and that the disruption is achieved by open reading frame 61 (ORF61) protein via its SUMO-interacting motifs (SIMs). Three conserved SIMs mediated ORF61 binding to SUMO1 and were required for ORF61 association with and disruption of PML NBs. Mutation of the ORF61 SIMs in the VZV genome showed that these motifs were necessary for PML NB dispersal in VZV-infected cells in vitro. In vivo, PML NBs were highly abundant, especially in basal layer cells of uninfected skin, whereas their frequency was significantly decreased in VZV-infected cells. In contrast, mutation of the ORF61 SIMs reduced ORF61 association with PML NBs, most PML NBs remained intact and importantly, viral replication in skin was severely impaired. The ORF61 SIM mutant virus failed to cause the typical VZV lesions that penetrate across the basement membrane into the dermis and viral spread in the epidermis was limited. These experiments indicate that VZV pathogenesis in skin depends upon the ORF61-mediated disruption of PML NBs and that the ORF61 SUMO-binding function is necessary for this effect. More broadly, our study elucidates the importance of PML NBs for the innate control of a viral pathogen during infection of differentiated cells within their tissue microenvironment in vivo and the requirement for a viral protein with SUMO-binding capacity to counteract this intrinsic barrier.

Cytomegalovirus infection presenting as isolated inflammatory polyps of the gastrointestinal tract.

BACKGROUND: Gastrointestinal involvement by cytomegalovirus (CMV) infection is a well recognised complication in patients taking steroid/immunosuppressive therapy or suffering from immunodeficiency and debilitating diseases. Rarely, CMV may affect immunocompetent healthy individuals. However, CMV infection presenting as isolated inflammatory polyps is unusual. METHODS: We describe five patients (1 infant and 4 adults 56-80 years of age) with CMV-associated polyps that posed diagnostic difficulty. Four lesions were initially misdiagnosed as inflammatory fibroid polyp (n = 2), atypical/suspicious lymphoproliferative (n = 1) and mesenchymal (n = 1) lesion. RESULTS: Underlying diseases were kidney transplantation (1), ulcerative colitis (1), and HIV infection (1). One elderly patient had pseudomembranous colitis but no significant co-morbidity. One patient had no relevant diseases. The lesions affected the colon (3), small intestine (1) and gastric antrum (1); one was multifocal. The size ranged from 0.3 cm to 2.0 cm. Histologically, all lesions showed extensive surface ulceration and abundant capillary-rich granulation tissue containing activated lymphoid cells, plasma cells, granulocytes, enlarged histiocytes and atypical fibroblasts. Eosinophils were prominent in two cases. Immunohistochemistry showed unequivocal intranuclear CMV inclusions. CONCLUSION: These cases widen the spectrum of endoscopic and histological appearance of gastrointestinal CMV infection. Awareness of these unusual lesions should enhance detection and proper classification of this probably under-recognised CMV presentation.

Crosstalk between viruses and PML nuclear bodies: a network-based approach.

Due to the recent advances in instrumental and scientific methods, cell biology data are generated with increasing speed and quantity. One of these fast developing fields is the crosstalk between promyelocytic leukemia protein nuclear bodies (PML-NBs) and viruses. PML-NBs are dynamic nuclear protein aggregates which are targeted by entire viral particles, viral proteins or viral nucleic acids. Their possible anti-viral properties motivated researchers to investigate the interaction between PML-NBs and viruses in depth. Based on extensive literature data mining, we created a comprehensive PML-NB/virus crosstalk Cytoscape network, which groups not only the most common relations but also less well described findings. The network is easy to navigate and provides a biologically relevant overview which can help finding interesting case studies.

Functional reorganization of promyelocytic leukemia nuclear bodies during BK virus infection.

BK virus (BKV) is the causative agent for polyomavirus-associated nephropathy, a severe disease found in renal transplant patients due to reactivation of a persistent BKV infection. BKV replication relies on the interactions of BKV with many nuclear components, and subnuclear structures such as promyelocytic leukemia nuclear bodies (PML-NBs) are known to play regulatory roles during a number of DNA virus infections. In this study, we investigated the relationship between PML-NBs and BKV during infection of primary human renal proximal tubule epithelial (RPTE) cells. While the levels of the major PML-NB protein components remained unchanged, BKV infection of RPTE cells resulted in dramatic alterations in both the number and the size of PML-NBs. Furthermore, two normally constitutive components of PML-NBs, Sp100 and hDaxx, became dispersed from PML-NBs. To define the viral factors responsible for this reorganization, we examined the cellular localization of the BKV large tumor antigen (TAg) and viral DNA. TAg colocalized with PML-NBs during early infection, while a number of BKV chromosomes were adjacent to PML-NBs during late infection. We demonstrated that TAg alone was not sufficient to reorganize PML-NBs and that active viral DNA replication is required. Knockdown of PML protein did not dramatically affect BKV growth in culture. BKV infection, however, was able to rescue the growth of an ICP0-null herpes simplex virus 1 mutant whose growth defect was partially due to its inability to disrupt PML-NBs. We hypothesize that the antiviral functions of PML-NBs are inactivated through reorganization during normal BKV infection.

Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus.

The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML-NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins.

Viral disruption of promyelocytic leukemia (PML) nuclear bodies by hijacking host PML regulators.

Epstein-Barr virus (EBV) latent infection promotes cell survival and proliferation, in some cases contributing to tumourigenesis. EBV-immortalized cells and EBV-induced tumours express the viral EBNA1 protein which, in addition to its roles in replicating and maintaining EBV genomes, can alter cellular processes, including the disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) through the degradation of PML proteins. PML NBs are based on PML proteins and mediate several cellular processes including apoptosis, DNA repair and antiviral responses. Accordingly, EBNA1 expression decreases apoptosis and DNA repair which may contribute to malignant transformation. The ability of EBNA1 to disrupt PML NBs has recently been shown to require EBNA1 binding to two host proteins, the protein kinase CK2 and deubiquitylating protein USP7/HAUSP, both of which are known to be partially associated with PML NBs. EBNA1 increases the association of both CK2 and USP7 with PML NBs and, as a result, increases phosphorylation of PML proteins by CK2, a modification that is known to trigger PML polyubiquitylation and degradation. Recent data also implicates USP7 as a negative regulator of PML proteins and nuclear bodies by a mechanism independent of its intrinsic ubiquitin cleavage activity. The results suggest that EBNA1 usurps two host PML regulators in order to promote degradation of PML proteins and loss of PML NBs.

Progressive multifocal leukoencephalopathy and promyelocytic leukemia nuclear bodies: a review of clinical, neuropathological, and virological aspects of JC virus-induced demyelinating disease.

Progressive multifocal leukoencephalopathy is a fatal viral-induced demyelinating disease that was once rare but has become more prevalent today. Over the past decades, much has been learned about the disease from molecular study of the etiological agent of the disease, JC virus. Recently, promyelocytic leukemia nuclear bodies (PML-NBs), punctuate structures for important nuclear functions in eukaryotic cells, were identified as an intranuclear target of JC virus infection. Neuropathologically, JC virus-infected glial cells display diffuse amphophilic viral inclusions by hematoxylin-eosin staining (full inclusions), a diagnostic hallmark of this disease. Recent results using immunohistochemistry, however, revealed the presence of punctate viral inclusions preferentially located along the inner nuclear periphery (dot-shaped inclusions). Dot-shaped inclusions reflect the accumulation of viral progeny at PML-NBs, which may be disrupted after viral replication. Structural changes to PML-NBs have been reported for a variety of human diseases, including cancers and neurodegenerative disorders. Thus, PML-NBs may provide clues to the further pathogenesis of JC virus-induced demyelinating disease. Here, we review what we have learned since the disease entity establishment, including a look at recent progress in understanding the relationship between JC virus, etiology and PML-NBs.

HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies.

Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) in early passage primary human keratinocytes as well as HPV-negative tumor cells. This activity was found to require sequences of HPV-16 E7 involved in degradation of the retinoblastoma tumor suppressor protein as well as regions in the COOH terminus. HPV-16 E7-induced APBs contained ssDNA and several proteins that are involved in the response to DNA replication stress, most notably the Fanconi anemia D2 protein (FANCD2) as well as BRCA2 and MUS81. In line with these results, we found that FANCD2-containing APBs form in an ATR-dependent manner in HPV-16 E7-expressing cells. To directly show a role of FANCD2 in ALT, we provide evidence that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. Taken together, our results suggest a novel link between replication stress and recombination-based telomere maintenance that may play a role in HPV-16 E7-mediated extension of host cell life span and immortalization.

New insights into the role of the subnuclear structure ND10 for viral infection.

Nuclear domains 10 (ND10), alternatively termed PML nuclear bodies (PML-NBs) or PML oncogenic domains (PODs), have been discovered approximately 15 years ago as a nuclear substructure that is targeted by a variety of viruses belonging to different viral families. This review will summarize the most important structural and functional characteristics of ND10 and its major protein constituents followed by a discussion of the current view regarding the role of this subnuclear structure for various DNA and RNA viruses with an emphasis on herpesviruses. It is concluded that accumulating evidence argues for an involvement of ND10 in host antiviral defenses either via mediating an intrinsic immune response against specific viruses or via acting as a component of the cellular interferon pathway.

Prominent eosinophilic intranuclear inclusions in melanocytes of a melanocytic nevus: the aftermath of an infection with molluscum contagiosum? A case report.

A 65-year-old Latino man presented to his dermatologist for the removal of two melanocytic nevi from the back. The first nevus was removed from the right scapula and contained melanocytes with prominent eosinophilic nuclear inclusion bodies. The second nevus was removed from the paravertebral region, without evidence of inclusion bodies. Ultrastructurally, the inclusions in the first nevus contained dispersed finely granular, homogenous bodies without a limiting membrane. Immunohistochemistry characterized them as ubiquitin-positive material. Reverse transcriptase in situ polymerase chain reaction analysis was positive for molluscum-specific primers, suggesting that the inclusions encountered in the first nevus were secondary to a remote, local molluscum viral infection of melanocytes.