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Chronic-dose acyclovir to suppress frequently recurring genital herpes simplex virus infection: effect on antibody response to herpes simplex virus type 2 proteins.

To determine the effect of prolonged suppressive acyclovir therapy on the antibody response to herpes simplex virus type 2 (HSV-2) proteins, we studied sequential sera from 33 patients with frequently recurring (six or more recurrences per year) genital herpes. Twenty-two patients received 400 mg of oral acyclovir and 11 received placebo, twice daily for one year. Sera collected at enrollment, after six months and 12 months of therapy, and during the first recurrence after cessation of therapy were evaluated by western blot for levels of antibodies to HSV-2, gB, gG, gC/gE, VP16, and gD. Mean levels declined by 27%-39% after one year of acyclovir. The magnitude of the decrease in antibody levels was not correlated with disease severity either during or after therapy. Patients with high relative antibody levels to gB after therapy had more-severe first recurrences after therapy than did patients with antibody levels to gB less than or equal to the median. Antibody levels were not restored after the first untreated recurrence.

Acyclovir↗

Induction of a latent herpes simplex virus from a rat tumour initiated by herpes simplex virus-transformed cells.

A rat tumour induced by cells transformed with the sheared DNA of herpes simplex virus (HSV) type 1 HFEM alpha (RE2A) was injected with the intertypic virus HSV-2 HG52 ts 1. Separate plaques, isolated from cocultivation of excised tumour tissue with susceptible cells, yielded virus the DNA of which had the restriction enzyme profile either of the injected HSV-2 virus or that of the HSV-1 virus, originally used to transform the cells. No evidence of in vivo recombination was detected. In Hooded Lister rats, HSV may have the ability to remain in a latent or non-replicating state in fibroblasts.

Animals↗

Modulation by cyclosporin A of murine natural resistance against herpes simplex virus infection. I. Interference with the susceptibility to herpes simplex virus infection.

Adult BALB/c mice which are medium-high resistant against intraperitoneal (i.p.) infection with herpes simplex virus type 2 (HSV-2) manifested a drastic increase in susceptibility to the virus when treated locally with cyclosporin A (CyA) during infection. Oral application of the drug had no effect on the natural resistance status. Mice appeared normal 2 weeks after CyA treatment with regard to their ability to resist i.p. infections. CyA did not interfere with established specific immune protection nor with the induction in immune responses to HSV-2.

Administration, Oral↗

Clinical evaluation of a new herpes simplex virus ELISA: a rapid diagnostic test for herpes simplex virus.

A new sensitive and rapid enzyme-linked immunosorbent assay (ELISA) test (Du Pont HERPCHEK) for the detection of herpes simplex virus (HSV) antigen was evaluated. A total of 563 clinical samples collected from patients attending obstetrics and gynecology and sexually transmitted disease clinics in two geographic locations were tested by ELISA, and the results were compared with virus isolation in cell culture. The sensitivity and specificity of the ELISA were 97.5 and 98.6%, respectively. When a confirmatory blocking ELISA was used to demonstrate the presence of HSV antigen in culture-negative but ELISA-positive samples, the specificity of the assay increased to 100%. The assay is easy to perform and may be used to diagnose HSV infection rapidly without the need for culture confirmation.

Adult↗

A combined indirect ELISA and immunoblotting for the detection of intrathecal herpes simplex virus IgG antibody synthesis in patients with herpes simplex virus encephalitis.

A combined indirect ELISA and immunoblotting assay was used for the detection of intrathecal synthesis of IgG antibodies to herpes simplex virus (HSV) in patients with HSV encephalitis (HSVE). By using these two assays as well as three markers for blood-brain barrier, leakage can be easily excluded. A total of 21 sera and 24 cerebrospinal fluid (CSF) samples from 11 patients with HSVE were examined. For seven patients more than one pair of serum and CSF were available. For one patient IgG antibodies began to be detectable in CSF after the sixth day from the onset of the disease. In the other 10 patients the intrathecal synthesis of HSV IgG antibodies was detected later than the sixth day and reached high optical density (OD) values after the 10th day from the onset of disease, at the earliest. In contrast, intrathecal HSV antibody synthesis was not found in specimens taken from 20 patients with acute meningitis who composed our negative control group. The use of a combined indirect ELISA and of an immunoblotting assay on a single dilution of serum and CSF for HSV IgG synthesis in the central nervous system (CNS) allowed the diagnosis of HSVE after the first week of disease.

Antibodies, Viral↗

Typing of clinical herpes simplex virus isolates with mouse monoclonal antibodies to herpes simplex virus types 1 and 2: comparison with type-specific rabbit antisera and restriction endonuclease analysis of viral DNA.

A total of 122 clinical isolates of herpes simplex virus (HSV) from 107 patients were typed by using an indirect immunoperoxidase technique with commercially available type-specific rabbit antisera, recently developed mouse monoclonal antibodies to HSV types 1 and 2, and restriction endonuclease analysis of viral DNA. With the commercially available type-specific rabbit antisera, 34% of clinical HSV isolates were of indeterminate type; 63% of them were typed as HSV type 1 and 37% as HSV type 2 by using monoclonal antibody and restriction enzyme typing systems. Typing by immunofluorescence assay with the monoclonal antibodies gave identical results to those obtained by restriction enzyme analysis. Simultaneous infection with both HSV types was demonstrated by monoclonal antibody typing in five isolates from three patients. These findings were subsequently confirmed by plaque purification and restriction endonuclease analysis of viral DNA. Monoclonal antibodies were as sensitive as restriction enzyme analysis for the typing of clinical HSV isolates. Because of their simplicity, they are more amenable to use in clinical laboratories than is restriction endonuclease analysis.

Animals↗

Different forms of membrane-associated herpes simplex virus glycoproteins induce functionally distinct subsets of herpes simplex virus-specific suppressor T cells.

Previous studies have shown that two types of virus-specific suppressor T cells (Ts) are induced in mice made tolerant with herpes simplex virus (HSV)-infected spleen cells (SC). One type of Ts blocks the afferent phase of the delayed hypersensitivity response to HSV (Ts-aff), and the other blocks the efferent or effector phase (Ts-eff). In this report we show that the induction requirements for these suppressor populations differ. Injection of SC infected for 6 h with HSV at a multiplicity of infection of 5 or less or treated with heat-inactivated virus induced only Ts-aff. Similar results were seen with SC incubated for 90 min in virus-free preparations containing only viral proteins. In contrast, the Ts-eff population was induced only by SC treated for 6 h with infectious HSV at a multiplicity of infection of 10. Collectively, these data indicate that Ts-aff are induced by adsorbed HSV antigens on SC, whereas Ts-eff are induced by nascent HSV antigens expressed on infected SC. In addition to their induction requirements, the two types of regulatory cells differ in their expression of effector function. Ts-eff but not Ts-aff require a cyclophosphamide-sensitive target cell in the immune recipient for suppressor function. The possible identity of this target cell and the significance of the different induction requirements between the two types of Ts are discussed.

Animals↗

Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2.

As measured by plaque and yield reduction assays, several metabolites of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) were highly active against herpes simplex virus types 1 and 2. These metabolites included the 2'-deoxy-2'-fluoroarabinosyl derivatives of 5-iodouracil (FIAU), cytosine (FAC), uracil (FAU), and thymine (FMAU). In mice inoculated intracerebrally with herpes simplex virus type 2, the relative order of potency of these compounds and licensed antiviral drugs was as follows: FMAU much greater than FIAC approximately equal to FIAU greater than acyclovir approximately equal to vidarabine much greater than FAC approximately equal to FAU. One of the main metabolites of FMAU, 2'-fluoro-5-hydroxymethyl-arabinosyluracil, was essentially inactive in vivo. FIAC-, FIAU-, FMAU-, FAC-, and FAU-resistant herpes simplex virus variants prepared in cell culture were found to be (i) devoid of viral thymidine kinase, (ii) cross-resistant to one another and resistant to drugs requiring viral thymidine kinase for activation, and (iii) sensitive to vidarabine or phosphonoformate. These results indicate that FIAC, FIAU, and FMAU require the virally encoded thymidine kinase for activation and suggest that the antiviral activity of FAU and FAC in cell cultures is also mediated by this enzyme. The interaction of the fluoroarabinosyl pyrimidine nucleosides with herpes simplex virus thymidine kinase in a cell-free system is also described.

Animals↗

Herpes simplex virus.

Herpes simplex virus (HSV) infection is prevalent worldwide. Herpes labialis, caused predominantly by HSV-1, and herpes vulvovaginitis, caused predominantly by HSV-2, may result in significant morbidity and mortality for infected neonates exposed during delivery. The diagnosis of HSV infection is made by serological testing, viral culture, or polymerase chain reaction. Women with primary herpes vulvovaginitis exhibit a painful vesicular rash which is self-limited but may be followed by multiple recurrences. Women at greatest risk to transmit HSV to their neonates are those who experience their first episode of HSV during the latter stage of pregnancy. If infected, their neonates may have localized skin, eye and mucosal lesions, invasive central nervous system infection, or disseminated disease. Because of the potentially devastating outcome for a baby infected with HSV, pregnant women with active HSV lesions at delivery should be offered a cesarean section. Still, many neonates who are infected with HSV are born to women with asymptomatic HSV shedding. Therefore, prevention of HSV during pregnancy is exceedingly important.

Female↗

Implications for herpes simplex virus vaccine strategies based on antibodies produced to herpes simplex virus type 1 glycoprotein gC immune evasion domains.

Herpes simplex virus type I (HSV-1) glycoprotein gC (gC-1) is an immune evasion molecule that inhibits complement activation by binding C3b. Three assays were used to assess whether IgG antibodies produced by HSV-1 infection in humans block the interaction between C3b and gC-1. In two assays human IgG had no effect, while in one assay IgG partially inhibited C3b binding, which occurred at IgG concentrations approaching the upper limits of those found in human serum. Mice infected with HSV-1 produced antibodies that partially blocked C3b binding at lower IgG concentrations than human IgG. Importantly, gC-1 immunization in mice produced higher titers of gC-1 antibodies than infection. We previously reported that gC-1 immunization in mice totally blocks C3b binding and reduces disease severity. Therefore, gC-1 immunization in humans may also induce blocking antibodies that modify disease, despite the rather limited ability of infection to produce these antibodies.

Animals↗

Typing of herpes simplex virus types 1 and 2 by immunoblotting analysis using polyclonal antisera to herpes simplex virus glycoproteins.

Herpes simplex virus (HSV) isolates were differentiated by immunoblotting analysis using a mixture of polyclonal antisera directed against HSV type 1 (HSV-1) and HSV type 2 (HSV-2) glycoprotein fractions (gB/gC of HSV-1 and gC/gE/84-kDa protein of HSV-2), since the mixed antisera recognized viral polypeptides with different molecular weights in HSV-1- and HSV-2-infected cells. Results of typing by immunoblotting analysis were consistent with those obtained by restriction endonuclease analysis of DNAs extracted from 10 HSV isolates. These results suggest that the immunoblotting technique will be applicable to reliable typing of HSV isolates using polyclonal antisera showing the difference in reaction patterns between HSV-1- and HSV-2-infected cells.

Animals↗

Extensive homology between the herpes simplex virus type 2 glycoprotein F gene and the herpes simplex virus type 1 glycoprotein C gene.

The region of the herpes simplex virus type 2 (HSV-2) genome which maps colinearly with the HSV-1 glycoprotein C (gC) gene has been cloned, and the DNA sequence of a 2.29-kilobase region has been determined. Contained within this sequence is a major open reading frame of 479 amino acids. The carboxyterminal three-fourths of the derived HSV-2 protein sequence showed a high degree of sequence homology to the HSV-1 gC amino acid sequence reported by Frink et al. (J. Virol. 45:634-647, 1983). The amino-terminal region of the HSV-2 sequence, however, showed very little sequence homology to HSV-1 gC. In addition, the HSV-1 gC sequence contained 27 amino acids in the amino-terminal region which were missing from the HSV-2 protein. Computer-assisted analysis of the hydrophilic and hydrophobic properties of the derived HSV-2 sequence demonstrated that the protein contained structures characteristic of membrane-bound glycoproteins, including an amino-terminal signal sequence and carboxy-terminal hydrophobic transmembrane domain and charged cytoplasmic anchor. The HSV-2 protein sequence also contained seven putative N-linked glycosylation sites. These data, in conjunction with mapping studies of Para et al. (J. Virol. 45:1223-1227, 1983) and Zezulak and Spear (J. Virol. 49:741-747, 1984), suggest that the protein sequence derived from the HSV-2 genome corresponds to gF, the HSV-2 homolog of HSV-1 gC.

Amino Acid Sequence↗

[What's new in vaccines against herpes simplex infections?].

Herpes simplex viruses (HSV) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy HSV infections remain a public health problem. Vaccines offer the possibility for controlling the spread and limiting HSV disease, two strategies for herpes vaccination: prophylactic immunization or therapeutic immunization. The article discusses the results of different studies, in particular, concerning recombinant vaccines, DISC vaccines and DNA vaccines.

Herpes Simplex↗