Metagenomic profiling of placental tissue suggests DNA virus infection of the placenta is rare

It is widely recognized that pathogens can be transmitted across the placenta from mother to foetus. Recent re-evaluation of metagenomic studies indicates that the placenta has no unique microbiome of commensal bacteria. However, viral transmission across the placenta, including transmission of DNA viruses such as the human herpesviruses, is possible. A fuller understanding of which DNA virus sequence can be found in the placenta is required. We employed a metagenomic analysis to identify viral DNA sequences in placental metagenomes from full-term births (20 births), pre-term births (13 births), births from pregnancies associated with antenatal infections (12 births) or pre-term births with antenatal infections (three births). Our analysis found only a small number of DNA sequences corresponding to the genomes of human herpesviruses in four of the 48 metagenomes analysed. Therefore, our data suggest that DNA virus infection of the placenta is rare and support the concept that the placenta is largely free of pathogen infection.

The Ins and Outs of Herpesviral Capsids: Divergent Structures and Assembly Mechanisms across the Three Subfamilies

Human herpesviruses, classified into three subfamilies, are double-stranded DNA viruses that establish lifelong latent infections within most of the world’s population and can cause severe disease, especially in immunocompromised people. There is no cure, and current preventative and therapeutic options are limited. Therefore, understanding the biology of these viruses is essential for finding new ways to stop them. Capsids play a central role in herpesvirus biology. They are sophisticated vehicles that shelter the pressurized double-stranded-DNA genomes while ensuring their delivery to defined cellular destinations on the way in and out of the host cell. Moreover, the importance of capsids for multiple key steps in the replication cycle makes their assembly an attractive therapeutic target. Recent cryo-electron microscopy reconstructions of capsids from all three subfamilies of human herpesviruses revealed not only conserved features but also remarkable structural differences. Furthermore, capsid assembly studies have suggested subfamily-specific roles of viral capsid protein homologs. In this review, we compare capsid structures, assembly mechanisms, and capsid protein functions across human herpesvirus subfamilies, highlighting the differences.

Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

Structure of human cytomegalovirus virion reveals host tRNA binding to capsid-associated tegument protein pp150

Under the Baltimore nucleic acid-based virus classification scheme, the herpesvirus human cytomegalovirus (HCMV) is a Class I virus, meaning that it contains a double-stranded DNA genome—and no RNA. Here, we report sub-particle cryoEM reconstructions of HCMV virions at 2.9 Å resolution revealing structures resembling non-coding transfer RNAs (tRNAs) associated with the virion’s capsid-bound tegument protein, pp150. Through deep sequencing, we show that these RNA sequences match human tRNAs, and we built atomic models using the most abundant tRNA species. Based on our models, tRNA recruitment is mediated by the electrostatic interactions between tRNA phosphate groups and the helix-loop-helix motif of HCMV pp150. The specificity of these interactions may explain the absence of such tRNA densities in murine cytomegalovirus and other human herpesviruses.

Olfactory entry promotes herpesvirus recombination

Herpesvirus genomes show abundant evidence of past recombination. Its functional importance is unknown. A key question is whether recombinant viruses can outpace the immunity induced by their parents to reach higher loads. We tested this by co-infecting mice with attenuated mutants of Murid Herpesvirus-4 (MuHV-4). Infection by the natural olfactory route routinely allowed mutant viruses to reconstitute wild-type genotypes and reach normal viral loads. Lung co-infections rescued much less well. Attenuated murine cytomegalovirus mutants similarly showed recombinational rescue via the nose but not the lungs. These infections spread similarly, so route-specific rescue implied that recombination occurred close to the olfactory entry site. Rescue of replication-deficient MuHV-4 confirmed this, showing that coinfection occurred in the first encountered olfactory cells. This worked even with asynchronous inoculation, implying that a defective virus can wait here for later rescue. Virions entering the nose get caught on respiratory mucus, which the respiratory epithelial cilia push back towards the olfactory surface. Early infection was correspondingly focussed on the anterior olfactory edge. Thus, by concentrating incoming infection into a small area, olfactory entry seems to promote functionally significant recombination. Importance All organisms depend on genetic diversity to cope with environmental change. Small viruses rely on frequent point mutations. This is harder for herpesviruses because they have larger genomes. Recombination provides another means of genetic optimization. Human herpesviruses often co-infect, and they show evidence of past recombination, but whether this is rare and incidental or functionally important is unknown. We showed that herpesviruses entering mice via the natural olfactory route meet reliably enough for recombination routinely to repair crippling mutations and restore normal viral loads. It appeared to occur in the first encountered olfactory cells and reflected a concentration of infection at the anterior olfactory edge. Thus, natural host entry incorporates a significant capacity for herpesvirus recombination.

The Impact of Human Herpesviruses in Clinical Practice of Inflammatory Bowel Disease in the Era of COVID-19

Human herpesviruses (HHVs): herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, HHV-7, and HHV-8, are known to be part of a family of DNA viruses that cause several diseases in humans. In clinical practice of inflammatory bowel disease (IBD), the complication of CMV enterocolitis, which is caused by CMV reactivation under disruption of intestinal barrier function, inflammation, or strong immunosuppressive therapy, is well known to affect the prognosis of disease. However, the relationship between other HHVs and IBD remains unclear. In the transplantation field, reactivation of other viruses, such as HHV-6, could cause colitis under immunosuppressed condition. Recent research revealed that combined infection of some HHVs could be a risk factor for colectomy in patients with ulcerative colitis. This suggests that it would be important to clarify HHV behavior in the treatment for patients with IBD, especially in those under immunosuppressive therapies. Looking at the relationship with recently emerged novel coronaviruses (SARS-CoV-2), there are reports describe that SARS-CoV-2 might induce reactivation of HSV-1, EBV, VZV (herpes zoster), and HHV-6/7. If SARS-CoV-2 infection becomes common, vigilance against HHV reactivation may become more crucial. In this review, we discuss the impact of HHVs in clinical practice of inflammatory bowel diseases, especially during the SARS-CoV-2 pandemic.

Atypical pityriasis rosea in a young Colombian woman. Case report

Introduction: Pityriasis rosea is an acute and self-limited exanthemfirst described by Gilbert in 1860. Its treatment is symptomatic, and although there is no conclusive evidence, it has been associated with the reactivation of the human herpesviruses 6 and 7 (HHV-6 and HHV-7). Case presentation: A 28-year-old woman, from Bogotá, Colombia, ahealth worker, attended the emergency room due to the onset ofsymptoms that began 20 days earlier with the appearance of punctiformlesions in the left arm that later spread to the thorax, abdomen, opposite arm, and thighs. The patient reported a history of bipolar II disorder and retinal detachment. After ruling out several infectious diseases, and due to the evolution of the symptoms, pityriasis rosea was suspected. Therefore, treatment was started with deflazacort 30mg for 21 days, obtaining a favorable outcome and improvement of symptoms after 2 months. At the time of writing this case report, the patient had not consulted for recurrence. Conclusion: Primary care physicians should have sufficient training indermatology to recognize and treat dermatological diseases since manyof them are diagnosed based on clinical findings. This is an atypicalcase, in which the patient did not present with some of the pathognomonic signs associated with pityriasis rosea.

Innate Immune Responses to Herpesvirus Infection

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response.