Recent Out-of-Africa Migration of Human Herpes Simplex Viruses

2020 ◽  
Vol 37 (5) ◽  
pp. 1259-1271 ◽  
Author(s):  
Diego Forni ◽  
Chiara Pontremoli ◽  
Mario Clerici ◽  
Uberto Pozzoli ◽  
Rachele Cagliani ◽  
...  
Keyword(s):  
Population Structure ◽  
Herpes Simplex ◽  
18Th Century ◽  
Molecular Dating ◽  
Human Pathogens ◽  
Herpes Simplex Viruses ◽  
Worldwide Distribution ◽  
Early Humans ◽  
Out Of Africa ◽  
Hsv 1

Abstract Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous human pathogens. Both viruses evolved from simplex viruses infecting African primates and they are thus thought to have left Africa during early human migrations. We analyzed the population structure of HSV-1 and HSV-2 circulating strains. Results indicated that HSV-1 populations have limited geographic structure and the most evident clustering by geography is likely due to recent bottlenecks. For HSV-2, the only level of population structure is accounted for by the so-called “worldwide” and “African” lineages. Analysis of ancestry components and nucleotide diversity, however, did not support the view that the worldwide lineage followed early humans during out-of-Africa dispersal. Although phylogeographic analysis confirmed an African origin for both viruses, molecular dating with a method that corrects for the time-dependent rate phenomenon indicated that HSV-1 and HSV-2 migrated from Africa in relatively recent times. In particular, we estimated that the HSV-2 worldwide lineage left the continent in the 18th century, which corresponds to the height of the transatlantic slave trade, possibly explaining the high prevalence of HSV-2 in the Americas (second highest after Africa). The limited geographic clustering of HSV-1 makes it difficult to date its exit from Africa. The split between the basal clade, containing mostly African sequences, and all other strains was dated at ∼5,000 years ago. Our data do not imply that herpes simplex viruses did not infect early humans but show that the worldwide distribution of circulating strains is the result of relatively recent events.

scholarly journals Herpes Simplex Virus Mistyping due to HSV-1 × HSV-2 Interspecies Recombination in Viral Gene Encoding Glycoprotein B

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 860
Author(s):  
Amanda M. Casto ◽  
Meei-Li W. Huang ◽  
Hong Xie ◽  
Keith R. Jerome ◽  
Anna Wald ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Recombination Event ◽  
Genomic Variation ◽  
Glycoprotein B ◽  
Viral Gene ◽  
Human Pathogens ◽  
Herpes Simplex Viruses ◽  
Single Nucleotide Change ◽  
Interspecies Recombination ◽  
Hsv 1

Human herpes simplex viruses (HSV) 1 and 2 are extremely common human pathogens with overlapping disease spectra. Infections due to HSV-1 and HSV-2 are distinguished in clinical settings using sequence-based “typing” assays. Here we describe a case of HSV mistyping caused by a previously undescribed HSV-1 × HSV-2 recombination event in UL27, the HSV gene that encodes glycoprotein B. This is the first documented case of HSV mistyping caused by an HSV-1 × HSV-2 recombination event and the first description of an HSV interspecies recombination event in UL27, which is frequently used as a target for diagnostics and experimental therapeutics. We also review the primer and probe target sequences for a commonly used HSV typing assay from nearly 700 HSV-1 and HSV-2 samples and find that about 4% of HSV-1 samples have a single nucleotide change in at least one of these loci, which could impact assay performance. Our findings illustrate how knowledge of naturally occurring genomic variation in HSV-1 and HSV-2 is essential for the design and interpretation of molecular diagnostics for these viruses.

scholarly journals Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

2016 ◽  
Vol 60 (4) ◽  
pp. 2140-2149 ◽  
Author(s):  
Peter J. Ireland ◽  
John E. Tavis ◽  
Michael P. D'Erasmo ◽  
Danielle R. Hirsch ◽  
Ryan P. Murelli ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Human Pathogens ◽  
Herpes Simplex Virus 1 ◽  
Herpes Simplex Viruses ◽  
Viral Shedding ◽  
Starting Point ◽  
Resistant Mutants ◽  
Low Cytotoxicity ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compounds inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

scholarly journals Characterization of Vesicular Stomatitis Virus Pseudotypes Bearing Essential Entry Glycoproteins gB, gD, gH, and gL of Herpes Simplex Virus 1

2016 ◽  
Vol 90 (22) ◽  
pp. 10321-10328 ◽  
Author(s):  
Henry B. Rogalin ◽  
Ekaterina E. Heldwein
Keyword(s):  
Herpes Simplex ◽  
Membrane Fusion ◽  
Viral Envelope ◽  
Herpes Simplex Virus 1 ◽  
Herpes Simplex Viruses ◽  
Systematic Exploration ◽  
Vesicular Stomatitis ◽  
Simplex Virus ◽  
First Time ◽  
Hsv 1

ABSTRACTHerpes simplex viruses (HSVs) are unusual in that unlike most enveloped viruses, they require at least four entry glycoproteins, gB, gD, gH, and gL, for entry into target cells in addition to a cellular receptor for gD. The dissection of the herpes simplex virus 1 (HSV-1) entry mechanism is complicated by the presence of more than a dozen proteins on the viral envelope. To investigate HSV-1 entry requirements in a simplified system, we generated vesicular stomatitis virus (VSV) virions pseudotyped with HSV-1 essential entry glycoproteins gB, gD, gH, and gL but lacking the native VSV fusogen G. These virions, referred to here as VSVΔG-BHLD virions, infected a cell line expressing a gD receptor, demonstrating for the first time that the four essential entry glycoproteins of HSV-1 are not only required but also sufficient for cell entry. To our knowledge, this is the first time the VSV pseudotyping system has been successfully extended beyond two proteins. Entry of pseudotyped virions required a gD receptor and was inhibited by HSV-1 specific anti-gB or anti-gH/gL neutralizing antibodies, which suggests that membrane fusion during the entry of the pseudotyped virions shares common requirements with the membrane fusion involved in HSV-1 entry and HSV-1-mediated syncytium formation. The HSV pseudotyping system established in this study presents a novel tool for systematic exploration of the HSV entry and membrane fusion mechanisms.IMPORTANCEHerpes simplex viruses (HSVs) are human pathogens that can cause cold sores, genital herpes, and blindness. No vaccines or preventatives are available. HSV entry into cells—a prerequisite for a successful infection—is a complex process that involves multiple viral and host proteins and occurs by different routes. Detailed mechanistic knowledge of the HSV entry is important for understanding its pathogenesis and would benefit antiviral and vaccine development, yet the presence of more than a dozen proteins on the viral envelope complicates the dissection of the HSV entry mechanisms. In this study, we generated heterologous virions displaying the four essential entry proteins of HSV-1 and showed that they are capable of cell entry and, like HSV-1, require all four entry glycoproteins along with a gD receptor. This HSV pseudotyping system pioneered in this work opens doors for future systematic exploration of the herpesvirus entry mechanisms.

scholarly journals Identification and Visualization of Functionally Important Domains and Residues in Herpes Simplex Virus Glycoprotein K(gK) Using a Combination of Phylogenetics and Protein Modeling

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Paul J. F. Rider ◽  
Lyndon M. Coghill ◽  
Misagh Naderi ◽  
Jeremy M. Brown ◽  
Michal Brylinski ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Evolutionary Rate ◽  
Quantitative Measure ◽  
Rate Variation ◽  
Human Pathogens ◽  
Herpes Simplex Viruses ◽  
Varicella Zoster ◽  
Conserved Sequence ◽  
Glycoprotein K ◽  
Herpes Simplex Virus Glycoprotein

Abstract Alphaherpesviruses are a subfamily of herpesviruses that include the significant human pathogens herpes simplex viruses (HSV) and varicella zoster virus (VZV). Glycoprotein K (gK), conserved in all alphaherpesviruses, is a multi-membrane spanning virion glycoprotein essential for virus entry into neuronal axons, virion assembly, and pathogenesis. Despite these critical functions, little is known about which gK domains and residues are most important for maintaining these functions across all alphaherpesviruses. Herein, we employed phylogenetic and structural analyses including the use of a novel model for evolutionary rate variation across residues to predict conserved gK functional domains. We found marked heterogeneity in the evolutionary rate at the level of both individual residues and domains, presumably as a result of varying selective constraints. To clarify the potential role of conserved sequence features, we predicted the structures of several gK orthologs. Congruent with our phylogenetic analysis, slowly evolving residues were identified at potentially structurally significant positions across domains. We found that using a quantitative measure of amino acid rate variation combined with molecular modeling we were able to identify amino acids predicted to be critical for gK protein structure/function. This analysis yields targets for the design of anti-herpesvirus therapeutic strategies across all alphaherpesvirus species that would be absent from more traditional analyses of conservation.

scholarly journals Characterization of Herpes Simplex Viruses Selected in Culture for Resistance to Penciclovir or Acyclovir

2001 ◽  
Vol 75 (4) ◽  
pp. 1761-1769 ◽  
Author(s):  
Robert T. Sarisky ◽  
Matthew R. Quail ◽  
Philip E. Clark ◽  
Tammy T. Nguyen ◽  
Wendy S. Halsey ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Sequence Similarity ◽  
Cross Resistance ◽  
Phenotypic Analysis ◽  
Herpes Simplex Viruses ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Penciclovir (PCV), an antiherpesvirus agent in the same class as acyclovir (ACV), is phosphorylated in herpes simplex virus (HSV)-infected cells by the viral thymidine kinase (TK). Resistance to ACV has been mapped to mutations within either the TK or the DNA polymerase gene. An identical activation pathway, the similarity in mode of action, and the invariant cross-resistance of TK-negative mutants argue that the mechanisms of resistance to PCV and ACV are likely to be analogous. A total of 48 HSV type 1 (HSV-1) and HSV-2 isolates were selected after passage in the presence of increasing concentrations of PCV or ACV in MRC-5 cells. Phenotypic analysis suggested these isolates were deficient in TK activity. Moreover, sequencing of the TK genes from ACV-selected mutants identified two homopolymeric G-C nucleotide stretches as putative hot spots, thereby confirming previous reports examining Acvr clinical isolates. Surprisingly, mutations identified in PCV-selected mutants were generally not in these regions but distributed throughout the TK gene and at similar frequencies of occurrence within A-T or G-C nucleotides, regardless of virus type. Furthermore, HSV-1 isolates selected in the presence of ACV commonly included frameshift mutations, while PCV-selected HSV-1 mutants contained mostly nonconservative amino acid changes. Data from this panel of laboratory isolates show that Pcvr mutants share cross-resistance and only limited sequence similarity with HSV mutants identified following ACV selection. Subtle differences between PCV and ACV in the interaction with viral TK or polymerase may account for the different spectra of genotypes observed for the two sets of mutants.

scholarly journals Structure of herpes simplex virus pUL7:pUL51, a conserved complex required for efficient herpesvirus assembly

2019 ◽  
Author(s):  
Benjamin G. Butt ◽  
Danielle J. Owen ◽  
Cy M. Jeffries ◽  
Lyudmila Ivanova ◽  
Jack W. Houghton ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cultured Cells ◽  
Virus Assembly ◽  
Human Pathogens ◽  
Direct Role ◽  
Virion Assembly ◽  
Animal Pathogens ◽  
Simplex Virus ◽  
Hsv 1

AbstractHerpesviruses are an ancient family of highly-prevalent human and animal pathogens that acquire their membrane envelopes in the cytoplasm of infected cells. While multiple conserved viral proteins are known to be required for efficient herpesvirus production, many of these proteins lack identifiable structural homologues and the molecular details of herpesvirus assembly remain unclear. We have characterized the complex of assembly proteins pUL7 and pUL51 from herpes simplex virus (HSV)-1, an α-herpesvirus, using multi-angle light scattering and small-angle X-ray scattering with chemical crosslinking. HSV-1 pUL7 and pUL51 form a stable 1:2 complex that is capable of higher-order oligomerization in solution. We solved the crystal structure of this complex, revealing a core heterodimer comprising pUL7 bound to residues 41–125 of pUL51. While pUL7 adopts a previously-unseen compact fold, the extended helix-turn-helix conformation of pUL51 resembles the cellular endosomal complex required for transport (ESCRT)-III component CHMP4B, suggesting a direct role for pUL51 in promoting membrane scission during virus assembly. We demonstrate that the interaction between pUL7 and pUL51 homologues is conserved across human α-, β- and γ-herpesviruses, as is their association with trans-Golgi membranes in cultured cells. However, pUL7 and pUL51 homologues do not form complexes with their respective partners from different virus families, suggesting that the molecular details of the interaction interface have diverged. Our results demonstrate that the pUL7:pUL51 complex is conserved across the herpesviruses and provide a structural framework for understanding its role in herpesvirus assembly.Significance StatementHerpesviruses are extremely common human pathogens that cause diseases ranging from cold sores to cancer. Herpesvirus acquire their membrane envelope in the cytoplasm via a conserved pathway, the molecular details of which remain unclear. We have solved the structure of a complex between herpes simplex virus (HSV)-1 proteins pUL7 and pUL51, two proteins that are required for efficient HSV-1 assembly. We show that formation of this complex is conserved across distantly-related human herpesviruses, as is the association of these homologues with cellular membranes that are used for virion assembly. While pUL7 adopts a previously-unseen fold, pUL51 resembles key cellular membrane-remodeling complex components, suggesting that the pUL7:pUL51 complex may play a direct role in deforming membranes to promote virion assembly.

scholarly journals Cell-to-cell spread inhibiting antibodies constitute a correlate of protection against Herpes Simplex Virus Type 1 reactivations

2020 ◽  
Author(s):  
Susanne Wolf ◽  
Mira Alt ◽  
Robin Dittrich ◽  
Miriam Dirks ◽  
Leonie Schipper ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Blood Donors ◽  
Vaccine Development ◽  
Natural Infection ◽  
Herpes Simplex Viruses ◽  
Correlate Of Protection ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

AbstractHerpes simplex viruses (HSV) cause ubiquitous human infections. For vaccine development, knowledge concerning correlates of protection against HSV is essential. Therefore, we investigated if humans principally can produce highly protective cell-to-cell spread inhibiting antibodies upon natural infection and whether such antibody responses correlate with protection from HSV reactivation. We established a high-throughput HSV-1 GFP reporter virus-based assay and screened 2496 human plasma samples for HSV-1 cell-to-cell spread inhibiting antibodies. We conducted a survey among the blood donors to analyze the correlation between the presence of cell-to-cell spread inhibiting antibodies in plasma and the frequency of HSV reactivations. In total, 128 of 2496 blood donors (5.1 %) exhibited high levels of HSV-1 cell-to-cell spread inhibiting antibodies in the plasma. Such individuals showed a significantly lower frequency of HSV reactivations compared to subjects without sufficient levels of HSV-1 cell-to-cell spread inhibiting antibodies. This study provides two important findings: (I) a fraction of humans produce HSV cell-to-cell spread inhibiting antibodies upon natural infection and (II) such antibodies correlate with protection against recurrent HSV. Moreover, these elite neutralizers can provide promising material for hyperimmunoglobulin, the isolation of superior antiviral antibodies and information for the design of a vaccine against HSV.ImportanceHerpes simplex virus 1 infections can cause painful mucosal lesions at the oral or genital tract and severe, life threatening disease in immunosuppressed patients or neonates. There is no approved vaccine available, and the emergence of drug resistances especially in long time treated patients makes the treatment increasingly difficult. We tested 2496 people for HSV-1 cell-to-cell spread inhibiting antibodies. Five percent exhibited functional titers such antibodies and showed significantly lower risk of reactivations, uncovering cell-to-cell spread inhibiting antibodies as a correlate of protection against Herpes simplex virus reactivations. Isolation of the cell-to-cell spread inhibiting antibodies from B-cells of these donors may contribute to develop novel antibody-based interventions for prophylactic and therapeutic use and provide starting material for vaccine development.

MOLECULAR DETECTION OF VIRUS HERPES SIMPLEX TYPE 1(HSV-1) , VIRUS HERPES SIMPLEX TYPE 2(HSV-2), CYTOMEGALOVIRUS(HCMV) and EPSTEIN-BARRVIRUS (EBV) IN SUPRA-GI

2018 ◽  
Vol 28 (2) ◽  
pp. 415-422
Author(s):  
Marija Ivanovska- Stojanoska ◽  
Mirjana Popovska ◽  
Violeta Anastasovska ◽  
Lindita Zendeli Bedjeti ◽  
Sashka Todorovska
Keyword(s):  
Herpes Simplex ◽  
Periodontal Disease ◽  
Dental Plaque ◽  
Molecular Detection ◽  
Herpes Simplex Type ◽  
Advanced Stage ◽  
Negative Finding ◽  
Herpes Simplex Viruses ◽  
Significant Difference ◽  
Hsv 1

Introduction Chronic periodontitis is as an inflammatory disease of the supporting tissue of the teeth caused by periopatogens microorganisams. New concept about etiology of periodontal disease suggests that herpes viruses may play an important role in the pathogenesis of periodontal disease. The aim of this study was to analyze the presence of herpes simplex virus type 1and 2 (HSV-1, HSV-2) cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), in supra-gingival dental plaque .Materials and Methods The study comprised a total of 89 patients who were divided in two groups: patients who were diagnosed moderate stage of periodontal disease and patients who were diagnosed with advanced stage of periodontal disease. Clinical examinations included determination of plaque index, gingival index, sulcus bleeding index, probing depth, and clinical attachment level. Supra-gingival dental plaque samples were taken with sterile coton ball scrub on tooth enamel. Molecular detection of HSV1, HSV2 , EBV and CMV was analyzed using polymerase chain reaction (PCR).Results Molecular analysis of HSV-1 ,HSV-2, EBV and CMV in supra-gingival dental plaque in patients with chronic periodontal disease (a total of 89) showed the presence of EBV in 12,40% of patients , HSV-1 was found in 11,20% of patients, in 7,90% of patients was detected HSV-2, CMV was established in 9,00% of patients. In 3,40% patients in supra-gingival dental plaque was detected combination of viruses HSV1 and CMV, in 3,40% of patient combination of HSV1 and EBV ; and in 2,20% of patient combination ofHSV2,EBV was observed; in 2,20% of patients was found combination of 3 viruses HSV1; HSV2; EBV and in 49,50% patients we found negative finding. Patients with moderate stage of periodontal disease have a 0,78 times(OR = 0,78 / 0,33-1,84/)no significantly lower risk of probability of finding viruses in the supra-gingival plaque compared to patients who had advanced stage of periodontal disease. In the shown cross-culture of the presence of viruses in supra-gingival plaque in patients with moderate and advanced stage of periodontal disease for Fisher, s Exact Test = 5,19 and p >0.05 (p = 0.809 / Monte Carlo sig. (0.799-0.819)there is no significant difference.Conclusion We can associate the presence of herpes simplex viruses in supra-gingival dental plaque with periodontal disease. Our findings suggest that there is no significant difference in presence of viruses in supra-gingival plaque in patients with moderate and sereve stage of periodontal disease.

Herpes Simplex Virus Infections: The Genital Tract and the Newborn

1992 ◽  
Vol 13 (3) ◽  
pp. 107-111
Author(s):  
Ann M. Arvin ◽  
Charles G. Prober
Keyword(s):  
Herpes Simplex ◽  
Host Immune System ◽  
Virus Infections ◽  
Human Herpes ◽  
Neonatal Infections ◽  
Herpes Simplex Viruses ◽  
Barr Virus ◽  
Source Of Infection ◽  
Herpes Group ◽  
Hsv 1

There are six recognized members of the human herpes group of viruses. These include type 1 and type 2 herpes simplex viruses (HSV-1 and HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicellazoster virus (VZV), and human herpes virus type 6 (HHV-6). These ubiquitous double-stranded DNA viruses are relatively large and lipid-enveloped. The capacity to induce a state of latency in the infected host has been proved for all of the herpes viruses. That is, after primary infection, the viruses remain forever with the host with the possibility for subsequent reactivations. The mechanisms of these reactivations are not understood completely. Both primary infections and recurrences may be associated with clinical illness or may be asymptomatic. To a large extent, the status of the host immune system determines the severity of the infection and the likelihood of recurrences. In general, infections are more severe and recurrences are more frequent in the most compromised hosts. This review focuses on HSV-1 and HSV-2, with emphasis on neonatal infections and maternal genital infections as a source of infection in the newborn. The clinical illnesses caused by HSV-1 and HSV-2 are usually quite distinct. HSV-1 is the predominant cause of oral, ocular, and central nervous system infections occurring after the neonatal period, and HSV-2 is the predominant cause of genital and neonatal infections.

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