BackgroundKaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are related human tumor viruses that cause primary effusion lymphomas (PEL) and Burkitt's lymphomas (BL), respectively. Viral genes expressed in naturally-infected cancer cells contribute to disease pathogenesis; knowing which viral genes are expressed is critical in understanding how these viruses cause cancer. To evaluate the expression of viral genes, we used high-resolution separation and mass spectrometry coupled with custom tiling arrays to align the viral proteomes and transcriptomes of three PEL and two BL cell lines under latent and lytic culture conditions.ResultsThe majority of viral genes were efficiently detected at the transcript and/or protein level on manipulating the viral life cycle. Overall the correlation of expressed viral proteins and transcripts was highly complementary in both validating and providing orthogonal data with latent/lytic viral gene expression. Our approach also identified novel viral genes in both KSHV and EBV, and extends viral genome annotation. Several previously uncharacterized genes were validated at both transcript and protein levels.ConclusionsThis systems biology approach coupling proteome and transcriptome measurements provides a comprehensive view of viral gene expression that could not have been attained using each methodology independently. Detection of viral proteins in combination with viral transcripts is a potentially powerful method for establishing virus-disease relationships.

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

Previous studies have shown that peptides containing the protein transduction domain (PTD) of the human immunodeficiency virus tat protein (GRKKRRQRRR) were effective inhibitors of herpes simplex virus type 1 (HSV-1) entry (H. Bultmann and C. R. Brandt, J. Biol. Chem. 277:36018-36023, 2002). We now show that the addition of a single cysteine residue to the C terminus of the TAT PTD (TAT-C peptide) improves the antiviral activity against HSV-1 and HSV-2. The principle effect of adding the cysteine was to enable the peptide to inactivate virions and to induce a state of resistance to infection in cells pretreated with peptide. The TAT-C peptide acted extracellularly, immediately blocked entry of adsorbed virus, prevented VP16 translocation to the nucleus, and blocked syncytium formation and cell-cell spread. Thus, TAT-C peptides are fusion inhibitors. The induction of the resistance of cells to infection was rapid, recovered with a half-life of 5 to 6 h, and could be reinduced by peptide treatment. TAT-C bound to heparan sulfate but was a poor competitor for viral attachment. The antiviral activity depended on the net positive charge of the peptide but not on chirality, and a free sulfhydryl group was not essential for antiviral activity because TAT-C dimers were at least as effective as monomers. The unique combination of antiviral activities and low toxicity combine to make TAT-C a strong candidate for further development as a drug to block HSV infection.Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are widespread human pathogens. Between 70 and 90% of adults in the United States are infected with HSV-1, and 22% of individuals over the age of 12 are seropositive for HSV-2 (7, 61). Both viruses infect mucous membranes causing ulcerative lesions that are usually self-limited in immunocompetent individuals. However, serious infections can occur, including lethal neonatal HSV, encephalitis, and blinding keratitis (34,61). A number of antivirals are approved for HSV treatment, and the use of these drugs has had a significant impact on the disease. These antivirals reduce the frequency of recurrent viral shedding and disease and reduce transmission of genital herpes between discordant partners (12,42,46). Although these treatment regimens significantly reduce disease, they are not completely effective and cannot clear latent infections. One significant problem in dealing with HSV infections is the ability of the virus to persist in the host in the form of latent infection (45). Preventing the establishment of a persistent infection, which could be accomplished either by blocking the initial infection or preventing the establishment of latency, would be ideal for dealing with this virus.One strategy for preventing infection is to block the attachment of virus. Attachment of HSV can be inhibited by heparin, which competes directly with the binding of gC and gB to cell surface heparan sulfate (HS) on cells (23,24,(26)(27)(28). Other polymeric anions and polyoxotungstate compounds have been shown to inhibit attachm...

Herpes simplex virus type 1 (HSV-1) envelope proteins are posttranslationally modified by the addition of sialic acids to the termini of the glycan side chains. Although gC, gD, and gH are sialylated, it is not known whether sialic acids on these envelope proteins are functionally important. Digestion of sucrose gradient purified virions for 4 h with neuraminidases that remove both ␣2,3 and ␣2,6 linked sialic acids reduced titers by 1,000-fold. Digestion with a ␣2,3-specific neuraminidase had no effect, suggesting that ␣2,6-linked sialic acids are required for infection. Lectins specific for either ␣2,3 or ␣2,6 linkages blocked attachment and infection to the same extent. In addition, the mobility of gH, gB, and gD in sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels was altered by digestion with either ␣2,3 specific neuraminidase or nonspecific neuraminidases, indicating the presence of both linkages on these proteins. The infectivity of a gC-1-null virus, ⌬gC2-3, was reduced to the same extent as wild-type virus after neuraminidase digestion, and attachment was not altered. Neuraminidase digestion of virions resulted in reduced VP16 translocation to the nucleus, suggesting that the block occurred between attachment and entry. These results show for the first time that sialic acids on HSV-1 virions play an important role in infection and suggest that targeting virion sialic acids may be a valid antiviral drug development strategy.Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen with 70 to 90% of the adults in the United States testing seropositive for the virus (92). The most common manifestation is mucous membrane infection resulting in ulcerative lesions that are usually self-limiting in immunocompetent individuals. However, serious illnesses, including lethal neonatal HSV, encephalitis, and blinding keratitis, can occur (43,49,83,92). Primary and recurrent infections in the immunocompromised, such as transplant recipients, those on chemotherapy, or those infected with human immunodeficiency virus (HIV) can be life-threatening (64,80,94). A number of antivirals are approved for HSV-1 treatment (21, 39, 60), but they are not completely effective. One significant problem in dealing with HSV infections is the ability of the virus to persist in the host as a latent infection (65). None of the currently available antivirals can eliminate a latent infection. Preventing the establishment of a persistent infection, which could be accomplished either by blocking infection or the establishment of latency, would be an ideal strategy for dealing with this virus.The development of agents to block HSV infection requires a greater understanding of HSV entry. Infection is initiated by the binding of viral glycoprotein C (gC) or gB to cell surface heparan sulfate proteoglycans (37,73,74). After attachment, gD can bind to any of several cellular receptors including herpes virus entry mediator, nectin-1, nectin-2, or 3-O-sulfated heparan sulfate (17,30,54,70,84), triggering a conformational change...