Incidence and Burden of Herpes Zoster in Sweden: A Regional Population-Based Register Study.

INTRODUCTION: Herpes zoster (HZ) is a painful disease that mainly affects individuals whose immune system has been weakened because of increasing age (> 50 years) or certain diseases or treatments. We estimated the complete burden of HZ. METHODS: This population-based register study analysed healthcare data from the VEGA and Digitalis databases of Västra Götaland Region (VGR), Sweden. The VEGA database includes all patients in VGR, covering both hospital and primary care. The Digitalis records prescribed medications. The study population included patients aged ≥ 18 years with at least one registered primary or secondary HZ diagnosis (based on International Classification of Diseases [ICD] codes) between 2005 and 2021. Incidence rates (95% confidence intervals [CI]) were stratified by age, sex and diagnosis/analgesic prescription. RESULTS: Overall HZ incidence increased from 2.5 (95% CI 2.4-2.6) in 2005 to 4.2 (95% CI 4.1-4.3) in 2021. The increase in incidence was rapid from 2005 to 2013, followed by a plateauing trend. From 2014-2019, the lifetime risk of HZ, excluding recurrent cases, was 36.5% (95% CI 35.5-37.4%). Municipal differences ranged from 34.4% (95% CI 32.5-36.4%) to 43.6% (95% CI 39.9-47.4%). Recurrence rates of HZ were 8.7% and 9.1% with follow-up periods of 5.5 and 10.5 years, respectively. Reported postherpetic neuralgia (PHN) cases increased five-fold over the study period. In 2019, 19% of all HZ patients developed HZ-related neuropathic pain; 13.6% had signs of persistent pain (> 90 days; i.e. PHN). An increased occurrence of cerebral and cardiovascular disease was observed in HZ patients. Among high-risk groups the occurrence of HZ peaked among those with inflammatory and autoimmune diseases. CONCLUSION: HZ and PHN risk in Sweden is comparable to that in other European countries prior to implementing HZ national vaccination programs. Municipal differences suggest that the lifetime risk of HZ in Sweden is at least 36.5%. CLINICAL TRIAL REGISTRATION: NCT Number ( www. CLINICALTRIALS: gov ).

What is the context?The varicella-zoster virus (VZV) can reactivate after primary infection and cause herpes zoster or shingles.Shingles is painful and mostly affects people aged > 50 years or those who have weakened immunity due to age, illness or medical treatments.The National Immunization Program (NIP) in Sweden does not currently include vaccination against shingles.We evaluated how often individuals from Västra Götaland Region, Sweden, experienced shingles and its complications.What is new?Overall, the number of shingles and PHN cases increased significantly from 2005 to 2021.We found that 14% of patients with shingles had pain persisting for > 3 months after a shingles episode.Most people developing shingles (about 70%) are healthy individuals without comorbidities, although those with underlying health issues have more risk of getting shingles.Over a follow-up period of 5.5 years, 8.7% of patients with shingles had more than one shingles episode.What is the impact?The occurrence of shingles and postherpetic neuralgia in Sweden is higher than what was reported previously and is comparable to other European countries before the implementation of shingles vaccination programmes.

Human antibodies to herpes simplex virus type 1 glycoprotein C are neutralizing and target the heparan sulfate-binding domain.

Human antibodies specific for glycoprotein C (gC1) of herpes simplex virus type 1 (HSV-1) neutralized the virus infectivity and efficiently inhibited attachment of HSV-1 to human HaCaT keratinocytes and to murine mutant L cells expressing either heparan sulfate or chondroitin sulfate at the cell surface. Similar activities were observed with anti-gC1 monoclonal antibody B1C1. In addition to HaCaT and L cells, B1C1 antibody neutralized HSV-1 infectivity in simian GMK AH1 cells mildly pre-treated with heparinase III. Human anti-gC1 antibodies efficiently competed with the binding of gC1 to B1C1 antibody whose epitope overlaps a part of the attachment domain of gC1. Human anti-gC1 and B1C1 antibodies extended survival time of mice experimentally infected with HSV-1. We conclude that in HaCaT cells and in cell systems showing restricted expression of glycosaminoglycans, human and some monoclonal anti-gC1 antibodies can target the cell-binding domain of this protein and neutralize viral infectivity.

Structural and functional features of the polycationic peptide required for inhibition of herpes simplex virus invasion of cells.

Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) mediates initial virus contact with cells by binding to heparan sulfate (HS) chains. The synthetic peptide 137GSRVQIRCRFRNSTR151 overlapping a major part of the HS-binding site of gC inhibited HSV-1 infection and, to some extent, HSV-2 infection of cells. Experiments on mutant, glycosaminoglycan-deficient cells as well as the binding assays involving peptide and purified cell surface components identified HS, and, to a lesser degree, chondroitin sulfate as sites of peptide activity. Anti-HSV-1 activity of the peptide was due to (i) partial inhibition of virus binding to cells and (ii) arresting the virions, which managed to attach to the cells in the presence of peptide, at a step of initial relatively weak binding. Analysis of the ionic-strength dependence of the peptide-HS and the virus-HS interactions revealed that the more efficient inhibition by the peptide of HSV-1 than HSV-2 infectivity was due to a relatively high affinity of HSV-2 for HS, a feature of importance in overcoming the peptide block. Mutational analysis of viral gC and peptide variants identified, apart from basic amino acids, two hydrophobic residues Ile(142) and Phe(146) as important in maintaining the specific affinity of peptide for HS and, hence, its anti-HSV activity. These results could contribute to the development of anti-HSV compounds that target initial events in the virus-cell interaction.

Basic amino acids as modulators of an O-linked glycosylation signal of the herpes simplex virus type 1 glycoprotein gC: functional roles in viral infectivity.

The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1 is engaged both in viral attachment and viral immune evasion mechanisms in the infected host. Besides several N-linked glycans, gC-1 contains numerous O-linked glycans, mainly localized in two pronase-resistant clusters in the N-terminal domain of gC-1. In the present study we construct and characterize one gC-1 mutant virus, in which two basic amino acids (114K and 117R) in a putative O-glycosylation sequon were changed to alanine. We found that this modification did not modify the N-linked glycosylation but increased the content of O-linked glycans considerably. Analysis of the O-glycosylation capacity of wild-type and mutant gC-1 was performed by in vitro glycosylation assays with synthetic peptides derived from the mutant region predicted to present new O-glycosylation sites. Thus the mutant peptide region served as a better substrate for polypeptide GalNAc-transferase 2 than the wild-type peptide, resulting in increased rate and number of O-glycan attachment sites. The predicted increase in O-linked glycosylation resulted in two modifications of the biological properties of mutant virus-that is, an impaired binding to cells expressing chondroitin sulfate but not heparan sulfate on the cell surface and a significantly reduced plaque size in cultured cells. The results suggested that basic amino acids present within O-glycosylation signals may down-regulate the amount of O-linked glycans attached to a protein and that substitution of such amino acid residues may have functional consequences for a viral glycoprotein involving virus attachment to permissive cells as well as viral cell-to-cell spread.

Herpes simplex virus type 1 glycoprotein C is necessary for efficient infection of chondroitin sulfate-expressing gro2C cells.

The role of glycoprotein C (gC) for binding of herpes simplex virus type 1 (HSV-1) to cell surface chondroitin sulfate (CS) and the consequences of this interaction for virus attachment and infectivity were studied. To this end, a panel of HSV-1 gC mutants, including a gC-negative (gC(-)) variant, and mouse fibroblasts expressing either cell surface CS or heparan sulfate (HS) were used. Comparing gC-positive (gC(+)) and gC(-) viruses in terms of their attachment to and infection of CS-expressing cells indicated that gC was essential for both functions. Furthermore, purified gC bound efficiently to isolated CS chains. However, hypertonic NaCl disrupted this interaction more easily as compared to the binding of gC to HS. Also, native and selectively desulfated heparins were approximately 10 times more efficient at inhibiting gC binding to CS-expressing cells than binding to HS-expressing cells. Experiments with the HSV-1 gC mutants revealed that specific, positively charged and hydrophobic amino acids within the N-terminal part of the protein were responsible for efficient binding as well as infectivity in both CS- and HS-expressing cells. When the infectivity of the gC mutants in the two cell types was compared, it appeared that more residues contributed to the infection of CS-expressing cells than to infection of HS-expressing cells. Taken together, analysis of gC function in cell systems with limited expression of glycosaminoglycans revealed that gC could interact with either CS or HS and that these interactions exhibited subtle but definite differences as regards to the involved structural features of gC, ionic strength dependency as well as sensitivity to specifically desulfated heparin compounds.

Mutational analysis of the major heparan sulfate-binding domain of herpes simplex virus type 1 glycoprotein C.

Heparan sulfate (HS) has been identified as a receptor molecule for numerous microbial pathogens, including herpes simplex virus type 1 (HSV-1). To further define the major HS-binding domain of the HSV-1 attachment protein, i.e. glycoprotein C (gC), virus mutants carrying alterations of either two neighbouring basic amino acid residues or a single hydrophobic amino acid residue within the N-terminal domain of the protein (residues 26-227) were constructed. In addition, a mutant lacking the Asn148 glycosylation site was included in the study. Binding of purified mutated gC proteins to isolated HS chains showed that viruses with mutations at residues Arg(129,130), Ile142, Arg(143,145), Arg(145,147), Arg(151,155) and Arg(155,160) had significantly impaired HS binding, in contrast to the other mutations, including Asn148. Impairment of the HS-binding activity of gC by these mutations had profound consequences for virus attachment and infection of cells in which amounts of HS exposed on the cell surface had been reduced. It is suggested that basic and hydrophobic residues localized at the Cys127-Cys144 loop of HSV-1 gC constitute a major HS-binding domain, with the most active amino acids situated near the C-terminal region of the two cysteines.