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the novel protein kinase of the rr1 subunit of herpes simplex virus has autophosphorylation and transphosphorylation activity that differs in its atp requirements for hsv-1 and hsv-2.the large subunit of herpes simplex virus (hsv) ribonucleotide reductase (rr1) designated icp6 and icp10 for hsv-1 and hsv-2, respectively, has a novel protein kinase (pk) enzymatic activity. icp10 is localized on the cell surface, a localization that depends on an intact transmembrane (tm) segment. we used immunocomplex pk assays to examine the pk activity of icp10 in stably transfected eukaryotic cells. activity was distinct from that of casein kinase ii (ckii) in that it did not require monov ...19968614985
characterization of an essential hsv-1 protein encoded by the ul25 gene reported to be involved in virus penetration and capsid assembly.the 2.3-kb bamhi-u dna fragment (map units 0.319-0.335) of herpes simplex virus type 1 (hsv-1) genome contains the complete ul25 open reading frame (orf). it specifies an essential viral protein reported previously to be involved in virus penetration and capsid assembly (c. addison, f. j. rixon, j. w. palfreyman, m. o'hara, and v. g. preston, virology 138, 246-259, 1984). to identify the protein encoded by the ul25 gene, the ul25 orf was cloned in a eukaryotic expression vector (p91023) downstre ...19968615003
human herpes simplex virus (hsv)-specific cd8+ ctl clones recognize hsv-2-infected fibroblasts after treatment with ifn-gamma or when virion host shutoff functions are disabled.herpes simplex virus (hsv)-specific cd8+ ctl cloned from individuals infected with hsv-2 efficiently lyse hsv-infected ebv-transformed b lymphoblastoid cells; however, these same ctl fail to lyse infected dermal fibroblasts. by 3 h after infection (early), class i mhc expression is reduced to less than 20% of that in uninfected fibroblasts, and expression is further reduced to less than 1% of the level in uninfected cells between 6 and 18 h after infection (late). we used an hsv-2 mutant that la ...19968621929
karalicin, a new biologically active compound from pseudomonas fluorescens/putida. ii. biological properties.the biological activities of karalicin, a new product from the pseudomonas fluorescens/putida strain ss-3 (ccm 4430) are described. it shows a weak, but specific and irreversible, antiviral activity on herpes simplex viruses. it also presents some inhibitory activity on different species of yeasts.19968626242
nucleic acid vaccine encoding gd2 protects mice from herpes simplex virus type 2 disease.nucleic acid vaccinations with plasmids pww65, containing the sequence for herpes simplex type 2 (hsv-2) gd2, and prsvnt, lacking the gd sequence, were studied. groups of mice were immunized with pww65 alone, pww65 plus 1,25-dihydroxyvitamin-d3 (d3), or prsvnt. clinical disease (vaginitis), serum and vaginal washing antibody levels, and vaginal washing virus titers were measured intravaginal hsv-2 challenge. no animals (0/10) in the pww65 + d3 group, 6/10 animals in the pww65 group, and 10/10 an ...19968627014
downstream regulatory elements increase acute and latent herpes simplex virus type 2 latency-associated transcript expression but do not influence recurrence phenotype or establishment of latency.the role of putative promoter or activator sequences downstream of the herpes simplex virus type 2 latency-associated transcript (lat) promoter and upstream of the lat intron was investigated in vivo by constructing and evaluating mutant viruses with deletions in this region. the deletion of lat promoter sequences upstream of the primary lat transcript reduced levels of lat expression during productive infections, compared with the lat expression level of wild-type virus, and abolished lat expre ...19968627672
locations of herpes simplex virus type 2 glycoprotein b epitopes recognized by human serum immunoglobulin g antibodies.herpes simplex virus type 2 (hsv-2) glycoprotein b (gb-2) gene segments were expressed as recombinant proteins in escherichia coli. gb-2 recombinant proteins were reacted with human serum immunoglobulin g (igg) antibodies in western immunoblot assays. initially, samples were tested for the presence of hsv-1-specific antibodies and hsv-2-specific antibodies by using hsv-infected cell lysates as antigen targets in western blot assays. serum samples that contained hsv-2-specific igg (n = 58), hsv-1 ...19968627770
antiviral activity of 9-[[(ethoxyhydroxyphosphinyl)-methoxy]methoxy] guanine against cytomegalovirus and herpes simplex virus.an isosteric analog of 9-[2-(phosphonomethoxy)ethyl]guanine (pmeg), 9-[[(ethoxyhydroxyphosphinyl)methoxy]methoxy]guanine (ski 1008), was evaluated for its in vitro antiviral activity against herpes simplex virus type 1 (hsv-1) and type 2 (hsv-2), murine cytomegalovirus (mcmv), and human cytomegalovirus (hcmv), and its in vivo antiviral efficacy against mcmv in mice. the in vitro anti-hsv activity of ski 1008 was much lower than that of acyclovir, even though ski 1008 showed similar antiviral act ...19958629816
synthesis and antiviral activity of pyranosylphosphonic acid nucleotide analogues.pyranosyl nucleotide analogues have been designed so that the intramolecular base to phosphorus distance closely approximates that of natural nucleotides. this was achieved by attaching the phosphorus directly at the anomeric position and the base at the 4-position of the carbohydrate. a series of compounds incorporating natural bases and having this novel structure were made via a short synthesis starting from commercially available glycals. addition of triisopropyl phosphite to the glycals fur ...19968632439
asymptomatic vaginal herpes simplex virus infections in mice: virology and pathohistology.one of the causes of genital tract infections in humans are herpes simplex virus types 1 and 2 (hsv-1, hsv-2). although primary and recurrent infections can be clinically apparent and in part very serious, many infections are asymptomatic and result only in temporary genital shedding of virus (recurrences). during our investigations of vaginitis, strain ies of hsv-1 produced an asymptomatic infection. replication in the murine vaginal (vag.) epithelium as well as antibody formation after vag. in ...19968634019
neonatal herpes simplex virus-2 encephalitis. 19958635813
herpes simplex virus type 2 infection associated with urinary retention in the absence of genital lesions.a 14-year-old boy had inguinal lymphadenitis and associated urinary retention; herpetic genital and anal lesions were absent. lymph node biopsy established the presence of infection with herpes simplex virus type 2. we recommend that this infection be considered in the differential diagnosis of adolescent patients with urinary retention and constipation, even when the diagnostic clue provided by genital ulcers is absent.19968636823
a herpesvirus inhibitor from bovine whey. 19968643002
serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis.infectious uveitis entities are usually rapidly progressive blinding diseases that can be prevented by prompt administration of specific antimicrobial therapy. with the aim of improving early diagnosis in patients with infectious uveitis, intraocular fluid samples from patients with sight-threatening posterior uveitis were investigated to determine the causative agent.19968644808
the activity of plant-derived antiretroviral proteins map30 and gap31 against herpes simplex virus in vitro.we examined the effect on anti-hiv proteins map30 and gap31, from momordica charantia and gelonium multiflorum, on the infection and replication of herpes simplex viruses (hsv). human lung wi-38 fibroblasts cultured in the presence of tenfold dilutions of map30 or gap31 were exposed to hsv and viral yield was measured at 24-48 hours by elisa. the effective concentrations for 50% inhibitions (ec50) were 0.1-0.2 microm for hsv-2, and 0.3-0.5 microm for hsv-1 for map30 and gap31, respectively. in c ...19968645280
differences in the susceptibility of herpes simplex virus types 1 and 2 to modified heparin compounds suggest serotype differences in viral entry.although heparan sulfate (hs) serves as an initial receptor for the binding of both herpes simplex virus type 1 (hsv-1) and hsv-2 to cell surfaces, the two serotypes differ in epidemiology, cell tropism, and ability to compete for viral receptors in vitro. these observations are not necessarily contradictory and can be explained if the two serotypes recognize different structural features of hs. to compare the specific features of hs important for the binding and infection of hsv-1 and hsv-2, we ...19968648678
structure-function analysis of soluble forms of herpes simplex virus glycoprotein d.glycoprotein d (gd) of herpes simplex virus (hsv) is essential for virus entry. truncated forms of gd lacking the transmembrane and cytoplasmic tail regions have been shown to bind to cells and block plaque formation. using complementation analysis and a panel of gd mutants, we previously identified four regions of gd (regions i to iv) which are important for virus entry. here, we used baculovirus vectors to overexpress truncated forms of wild-type gd from hsv type 1 (hsv-1) [gd-1(306t)] and hsv ...19968648717
[polymerase chain reaction assay of hsv in the rapid diagnosis of encephalitis]. 19958654268
prevalence of antibodies to herpes simplex virus types 1 and 2, epstein-barr virus and cytomegalovirus in teenage girls.seropositivity to herpes virus type 1 (hsv-1), herpes virus type 2 (hsv-2), cytomegalovirus (cmv) and epstein-barr virus (ebv) was estimated in a group of 98 16-year-old swedish girls. antibodies to hsv-1 were seen in 41% of the girls and to hsv-2 in 1%, and antibodies to cmv in 45 and to ebv in 82%. in girls with coitus experience, there was significantly higher prevalence of hsv-1 and ebv antibodies, compared with girls with no sexual contact. the age of coitarche or number of coitus partners ...19958658062
acquired immunodeficiency syndrome--associated herpes simplex virus retinitis. clinical description and use of a polymerase chain reaction--based assay as a diagnostic tool.to describe 2 patients with acquired immunodeficiency syndrome who experienced a rapidly progressive, bilateral retinitis due to herpes simplex virus (hsv) (1 case due to hsv type 1 [hsv-1] and 1 case due to hsv type 2 [hsv-2] and to present a novel diagnostic polymerase chain reaction (pcr)-based assay.19968660167
variability of herpes simplex virus 1 gl and anti-gl antibodies that inhibit cell fusion but not viral infectivity.herpes simplex virus type 1 gl lacks a transmembrane domain but stably associates with membranes through its oligomerization with the integral membrane glycoprotein designated gh. the gh-gl oligomers are essential for virion infectivity and virus-induced cell fusion. monoclonal and polyclonal antibodies were raised against hsv-1(kos) gl as probes for antigenic structure and functional protein domains. antigenic determinants recognized by these antibodies were found to be present on gl expressed ...19968661409
atp and sh3 binding sites in the protein kinase of the large subunit of herpes simplex virus type 2 of ribonucleotide reductase (icp10).the large subunit of herpes simplex virus type 2 ribonucleotide reductase (icp10) is a multifunctional protein. it consists of a ribonucleotide reductase and a serine/threonine protein kinase (pk) domain, which has three proline-rich motifs consistent with sh3-binding sites at positions 140, 149, and 396. we used site-directed mutagenesis to identify amino acids required for kinase activity and interaction with signaling proteins. mutation of lys176 or lys259 reduced pk activity (5-8-fold) and b ...19968663276
cervical cancer: is herpes simplex virus type ii a cofactor?in many ways, cervical cancer behaves as a sexually transmitted disease. the major risk factors are multiple sexual partners and early onset of sexual activity. although high-risk types of human papillomaviruses (hpv) play an important role in the development of nearly all cases of cervical cancer, other sexually transmitted infectious agents may be cofactors. herpes simplex virus type 2 (hsv-2) is transmitted primarily by sexual contact and therefore has been implicated as a risk factor. severa ...19958665469
hydrocephalus induction in mice infected with herpes simplex virus type 2 after antiviral treatment.by using antiviral chemotherapy to moderate the lethal effect of wild-type herpes simplex virus type 2 (hsv-2), a new mouse model for herpes simplex virus (hsv)-induced hydrocephalus was developed. groups of balb/c mice were infected either intracerebrally (i.c.) or intraperitoneally (i.p.) with a lethal dose of hsv-2. the antiviral agent 2'-fluoro-5-methylarabinosyluracil (fmau) was administered i.p. 2 days after virus inoculation. by day 21, 80 and 71.4% of the mice infected i.c. or i.p., resp ...19958669889
[antiviral activity of tannin from the pericarp of punica granatum l. against genital herpes virus in vitro].based on cell culture techniques this study has demonstrated that tannin from the pericarp of punica granatum is an effective component against genital herpes virus (hsv-2). the tannin not only inhibits hsv-2 replication, but also shows stronger effects of killing virus and blocking its absorption to cells.19958679095
meisenheimer rearrangement of azetopyridoindoles. viii. synthesis and antiviral activities of 12-carbaeudistomin analogs.eudistomins, isolated from the colonial tunicate eudistoma olivaceum, have been a synthetic target due to their strong antiviral activity against herpes simplex virus (hsv-1) and activities against certain types of tumors in vivo. in order to examine the structure-activity relationship of eudistomins, 12-carbaeudistomin analogs were synthesized and their activities against influenza a and b virus, hsv-1, hsv-2 and human cytomegalovirus were investigated. among them, racemic 6-methoxy-12-carbaeud ...19968689725
comparison of a dna probe assay with the plaque reduction assay for measuring the sensitivity of herpes simplex virus and varicella-zoster virus to penciclovir and acyclovir.a dna probe assay was compared with the plaque reduction assay to determine the sensitivity of clinical isolates of herpes simplex virus (hsv) and varicella-zoster virus (vzv) to penciclovir and acyclovir in mrc-5 cells. in both assays, penciclovir and acyclovir shared comparable activity against cell-free virus (cfv) preparations of vzv and herpes simplex virus type 1 (hsv-1) isolates, whilst acyclovir was significantly more active than penciclovir against herpes simplex virus type 2 (hsv-2) is ...19968690764
therapeutic potential of cidofovir (hpmpc, vistide) for the treatment of dna virus (i.e. herpes-, papova-, pox- and adenovirus) infections.(s)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (hpmpc, cidofovir, vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity against a wide variety of dna viruses including herpesviruses [herpes simplex virus type 1 (hsv-1) and type 2 (hsv-2), varicella-zoster virus (vzv), cytomegalovirus (cmv), epstein-barr virus (ebv), human herpesvirus type 6 (hhv-6) and equine and bovine herpesviruses], papovaviruses [human polyoma virus and human papilloma virus (hpv)], adeno-, irido-, ...19968701600
peptide sequences of glycoprotein g-2 discriminate between herpes simplex virus type 2 (hsv-2) and hsv-1 antibodies.the complete herpes simplex virus type 2 envelope glycoprotein g was represented by overlapping synthetic peptides. herpes simplex virus type 2-specific human seroreactivities were mainly seen against three peptides, peptides g2-64, g2-69, and g2-70, located in the c-terminal part of glycoprotein g. this is, interestingly, a region which has strong homology between herpes simplex virus types 1 and 2. g2-69 was the most herpes simplex virus type 2-specific peptide, reacting with 93% (13 of 14) of ...19968705666
isolation of pyropheophorbide a from the leaves of atalantia monophylla (roxb.) corr. (rutaceae) as a possible antiviral active principle against herpes simplex virus type 2.antiviral activity-guided isolation studies on the leaves of atalantia monophylla (roxb.) corr. (rutaceae) led to the identification of pyropheophorbide a (1), a simple chlorin derivative, from the chloroform extract (fr. b) as a possible antiviral active principle against herpes simplex virus type 2 (hsv-2). pyropheophorbide a methyl ester (2) was also isolated from the hexane extract (fr. a).19968706147
a comparison of referral patterns and characteristics of patients with first episode symptomatic genital hsv-1 and hsv-2 infections in sheffield.to ascertain factors associated with hsv-1 and hsv-2 isolates in patients attending a genitourinary medicine clinic with symptomatic first episode genital herpes (fegh).19968707325
activity of penciclovir in antiviral assays against herpes simplex virus.the effect of penciclovir and acyclovir on the replication of herpes simplex virus type 1 (hsv-1) and type 2 (hsv-2) strains was determined in mrc-5 cells infected with 0.01 pfu/cell and exposed to the drugs for 72 h to allow multiple cycles of replication. penciclovir was significantly more active than acyclovir against three strains of hsv-1 and three strains of hsv-2 at 1 mg/l (p = 0.009), 3 mg/l (p < 0.001) and 10 mg/l (p = 0.001). further comparisons between the compounds were made in mrc-5 ...19968707740
highly virulent strains of herpes simplex virus fail to kill mice following infection via gingival route.virulence of herpes simplex virus (hsv) in mice has been demonstrated to be dependent on the site of infection. in this experiment, pathogenesis of hsv was studied in 2 different routes of infection in a mouse model system. when balb/c mice were infected with 5 x 10(3) plaque-forming units (pfu) of virulent hsv type 1 miyama gc+ strain (hsv-1-gc+) intraperitoneally, all mice were dead in 6 to 9 days. hsv-1-gc+ was recovered from organs such as the cerebrum, cerebellum, brainstem, and spleen 2 to ...19968708138
herpes encephalitis is a disease of middle aged and elderly people: polymerase chain reaction for detection of herpes simplex virus in the csf of 516 patients with encephalitis. the study group.to assess the diagnostic potential of the polymerase chain reaction (pcr) in herpes simplex virus (hsv) encephalitis.19968708648
immunohistochemical studies on the transneuronal spread of virulent herpes simplex virus type 2 and its us3 protein kinase-deficient mutant after ocular inoculation.the transneuronal spread of a virulent wild-type herpes simplex virus type 2 (hsv-2) and its us3 protein kinase-deficient (us3 pk-) mutant was immunohistochemically studied in mice after inoculations into the cornea, anterior chamber, tongue, and masseter muscle. after corneal inoculation, the wild-type virus was demonstrated in various brain stem areas including the trigeminal tract and nucleus, the reticular formation, and cerebellar nucleus group. viral antigen-positive neurons were strictly ...19968709864
induction of cytotoxic t lymphocytes by intramuscular immunization with plasmid dna is facilitated by bone marrow-derived cells.striated muscle is the predominant site of gene expression after i.m. immunization of plasmid dna, but it is not clear if myocytes or professional antigen-presenting cells (apcs) of hematopoietic origin present the encoded antigens to class i major histocompatibility complex (mhc)-restricted cytotoxic t lymphocytes (ctl). to address this issue, ctl responses were assessed in mice engrafted with immune systems that were partially mhc matched with antigen-producing muscle cells. spleen cells (sc) ...19968710913
gender differences in sexual practices and sexually transmitted infections among adults in lima, peru.this study examined the prevalences of antibodies to treponema pallidum, chlamydia trachomatis, and herpes simplex virus type 2 in a sample of peruvian adults.19968712268
deletion of the carboxy-terminus of herpes simplex virus type 1 (hsv-1) glycoprotein b does not affect oligomerization, heparin-binding activity, or its ability to protect against hsv challenge.a recombinant vaccinia virus designated vgbt which expresses a truncated secreted herpes simplex virus gb (gbt) was constructed and compared to v11gb, a vaccinia recombinant previously studied which expresses gb exclusively on the surface of infected cells. indirect immunofluorescence assay (ifa) revealed that gbt was strongly associated with the surface of infected cells despite being released slowly into the cell culture medium. both gb and gbt existed as oligomers, and both membrane bound and ...19968712932
immunomodulatory effects of hsv2 glycoprotein d in hsv1 infected mice: implications for immunotherapy of recurrent hsv infection.immunological analyses in this laboratory and others have suggested that a nonrecurrent hsv seropositive immune status is more closely correlated with a type 1 t helper cell (th1) response characterized by elevated levels of interferon-gamma and il2 rather than high titers of virus-specific antibodies. effective intervention with an immunotherapeutic vaccine may require modulation of the regulatory network of t helper cells such that there is selective restimulation and expansion of the th1 resp ...19958719523
herpesvirus infections of the vulva. 19968723819
detection of viral antigen in the endolymphatic sac.a study was devised to determine whether or not any immune defense mechanism is present when a virus invades the human endolymphatic sac (es). the es was removed from 14 fresh autopsy cases having no known pre-mortem diseases in the middle and inner ears. specimens were then examined for viral antigens including herpes simplex (hsv) type 1 and 2, mumps and cytomegalovirus using immunohistochemical methods. dna examination by in situ hybridization was also performed for hsv. hsv antigen and dna w ...19968737782
recurrent meningitis and encephalitis associated with herpes simplex type 2: demonstration by polymerase chain reaction. 19968738952
famciclovir: review of clinical efficacy and safety.famciclovir is the well-absorbed oral form of penciclovir, an antiviral agent with potent activity against varicella-zoster virus (vzv) and herpes simplex virus (hsv-1) and 2 (hsv-2). after oral administration, famciclovir is rapidly converted to penciclovir with a bioavailability of 77%. penciclovir is efficiently phosphorylated to the active metabolite, penciclovir-triphosphate, and has a prolonged intracellular half-life of approximately 9-10 h in vzv-infected cells, and 10 and 20 h in cells ...19968739594
[a case of neonatal herpes infection which proved to be a mixed infection of herpes simplex virus type 1 and type 2].we encountered a case which proved to be a mixed infection of herpes simplex virus (hsv) type 1 and type 2 in retrospective terms by in situ hybridization (ish) and polymerase chain reaction (pcr). the case was a male. the gestational age was 39 weeks and 2 days. the birth body weight was 3024 g. a fever developed from the age of 6 days and he was admitted to the neonatal intensive care unit at the age of eight days. ast was 1042 iu/l, and alt 206 iu/l. in spite of treatment, the patient died at ...19968741714
immunotherapy with low-dose interleukin-2 and interferon-gamma in a murine tumor model.the aim of this study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (il-2) alone or together with interferon-gamma (ifn-gamma) in a herpes simplex virus type 2-transformed murine (h238) fibrosarcoma model. in vitro incubation showed that il-2, but not ifn-gamma, had a significant inhibitory effect on dna synthesis in h238 cells. in vivo experiments were performed with balb/c mice to determine the optimal time of treatment with each cytokine after subcuta ...19958746782
simultaneous pcr detection of haemophilus ducreyi, treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers.a multiplex pcr (m-pcr) assay with colorimetric detection was devised for the simultaneous amplification of dna targets from haemophilus ducreyi, treponema pallidum, and herpes simplex virus (hsv) types 1 and 2. by using target-specific oligonucleotides in a microwell format, 298 genital ulcer swab specimens collected in new orleans during three intervals from 1992 through 1994 were evaluated. the results of the m-pcr assay were compared with the results of dark-field microscopy and h. ducreyi c ...19968748271
[the relationship between placental pathology and certain pathogens detected in paraffin-embedded tissues in cases of intrauterine growth retardation].to study the relationship between placental pathology and certain pathogens detected in paraffin-embedded placental tissues in cases of intrauterine growth retardation (iugr).19968758801
the characteristic site-specific reactivation phenotypes of hsv-1 and hsv-2 depend upon the latency-associated transcript region.after replication at sites of initial inoculation, herpes simplex virus type 1 and 2 (hsv-1 and hsv-2) establish lifelong latent infections of the sensory and autonomic neurons of the ganglia serving those sites. periodically, the virus reactivates from these neurons, and travels centripetally along the neuronal axon to cause recurrent epithelial infection. the major clinically observed difference between infections with herpes simplex virus type 1 and type 2 is the anatomic site specificity of ...19968760819
disulfide bond structure determination and biochemical analysis of glycoprotein c from herpes simplex virus.a biochemical analysis of glycoprotein c (gc of herpes simplex virus was undertaken to further characterize the structure of the glycoprotein and to determine its disulfide bond arrangement. we used three recombinant forms of gc, gc1(457t), gc1(delta33-123t), and gc2(426t), each truncated prior to the transmembrane region. the proteins were expressed and secreted by using a baculovirus expression system and have been shown to bind to monoclonal antibodies which recognize discontinuous epitopes a ...19968764057
synthesis of 2'-aminomethyl derivatives of n-(2-(phosphonomethoxy)ethyl) nucleotide analogues as potential antiviral agents.a series of purine and pyrimidine n-(2-(phosphonomethoxy)ethyl) derivatives bearing aminomethyl, (dimethylamino)methyl, morpholinomethyl, and (trimethylammonio)methyl groups at the 2'-position were synthesized. the compounds were prepared by alkylation of the heterocyclic bases with appropriately substituted (aminoalkyl)oxiranes followed by condensation of the resulting intermediates with dialkyl ((p-tolylsulfonyl)oxy)methanephosphonate and subsequent treatment of the obtained diester with bromo ...19968765509
synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2.the synthesis of some new aminoadamantane derivatives is described. the new compounds were evaluated against a wide range of viruses [influenza a h1n1, influenza a h2n2, influenza a h3n2, influenza b, parainfluenza 3, herpes simplex virus type 1 (hsv-1) and type 2 (hsv-2), thymidine kinase-deficient (tk-) hsv-1, vaccinia, vesicular stomatitis, polio 1, coxsackie b4, sindbis, semliki forest, reo 1, varicella-zoster virus (vzv), tk- vzv, human cytomegalovirus (hcmv), and human immunodeficiency vir ...19968765514
relationship between antibodies to herpes simplex virus (hsv) and symptoms of hsv infection.to determine the relationship between antibodies to herpes simplex virus (hsv) types 1 and 2 and diagnosis of orolabial and genital herpes, a cross-sectional survey was done among 869 sexually transmitted disease clinic attendees and 1594 blood donors in london. among clinic attenders, the prevalence of hsv-1 infection was 59.5% and that of hsv-2 infection was 22.7%, and among blood donors the prevalence was 44.6% and 7.6%, respectively. the sensitivity and specificity of a diagnosis of oral her ...19968769602
spontaneous reactivation of thymidine kinase-deficient, acyclovir-resistant type-2 herpes simplex virus: masked heterogeneity or reversion?herpes simplex virus (hsv) strain 1737, acyclovir-resistant and uniformly thymidine kinase-deficient (tkd) by all conventional assays, clinically reactivated in an aids patient in the absence of antiviral drug pressure. investigation of its neurovirulence and latency characteristics in a mouse model using a tkd plaque isolate (1737-14), however, yielded a neurovirulent, homogeneous, acyclovir-sensitive, tk wild type (tkwt) strain (1737-14me), while trigeminal ganglia from a surviving animal yiel ...19968769603
antiviral properties of extract of opuntia streptacantha.an extract of the cactus plant opuntia streptacantha inhibited intracellular virus replication and inactivated extracellular virus. inhibition of virus replication also occurred following pre-infection treatment--a favourable finding in terms of in-vivo limitation of virus disease. there was inhibition of both dna and rna virus replication, for example, herpes simplex virus, equine herpes virus, pseudorabies virus, influenza virus, respiratory syncytial virus and human immunodeficiency virus, wi ...19968783800
detection of a transforming fragment of herpes simplex virus type 2 in clinical specimens by pcr. the canadian women's hiv study group.a pcr assay for the sensitive detection of a transforming fragment of herpes simplex virus type 2 (hsv-2) was developed. oligonucleotide primers were selected in xho-2, a transforming region of the bglii n fragment of hsv-2. the assay reached a sensitivity endpoint of 10 copies of the xho-2 subfragment and did not show cross-reactivity with other herpesviruses, including hsv-1. all 42 hsv-2 isolates scored positive in the assay. the xho-2 pcr assay was evaluated with 216 clinical specimens and t ...19968784564
disseminated herpes simplex virus infection presenting as fever in the newborn--a lethal outcome.the clinical course of a neonate who presented with fever and tachypnea on day 6 of life is described. he developed disseminated intravascular coagulopathy, hepatic failure, coma and expired at 14 days of age. the post mortem viral cultures from liver, adrenal and lungs were positive for hsv type 2. the fatal outcome of this case of fever, due to hsv infection, emphasizes the need for early treatment of suspicious cases of hsv infection. hsv should be considered in the differential diagnosis of ...19968793716
recurring episodes of meningitis (mollaret's meningitis) with one showing an association with herpes simplex virus type 2.benign recurrent aseptic (mollaret's) meningitis is a rare disease of unknown aetiology. we report the case of a 27-year-old woman who experienced three episodes of lymphocytic meningitis. human simplex virus (hsv) type 2 dna was detected in the csf by pcr amplification indicating the diagnosis of recurrent hsv type 2 meningitis. our observation suggests that search of herpes virus dna by pcr amplification on csf may be useful in unexplained recurrent meningitis.19968793718
detection of herpes simplex virus dna in cerebrospinal fluid samples using the polymerase chain reaction and microplate hybridization.as conventional polymerase chain reaction (pcr) procedures are time-consuming and laborious, we developed and evaluated a rapid semi-automatic microplate method to detect the amplified pcr products. the use of pcr, with subsequent hybridization in microplates, is described for the detection of herpes simplex virus (hsv) dna in cerebrospinal fluid samples. the principle of the method is based on two phases. firstly, the amplification of the viral dna in the sample is undertaken using a pair of pr ...19968793825
new antiherpesvirus agents. their targets and therapeutic potential.of the large number of agents under development for the treatment of herpes virus infections [herpes simplex virus types 1 and 2 (hsv-1 and hsv-2), varicella zoster virus (vzv), cytomegalovirus (cmv), epstein-barr virus (ebv)], only ten have apparently reached clinical development. aciclovir was approved for the treatment of hsv infections over 10 years ago, and it remains an important and reliable antiviral agent. recent approvals in some countries of valaciclovir for vzv infection and famciclo ...19968799682
effect of age and route of inoculation on outcome of neonatal herpes simplex virus infection in guinea pigs.the morbidity and mortality of neonatal herpes simplex virus infection remains unacceptably high despite antiviral therapy. a better understanding of factors that might contribute to this poor outcome is needed but has been hindered by a lack of a good animal model. the recently described guinea pig model of neonatal hsv-2 infection was used to explore the effect of age and route of inoculation on the outcome of infection. after intranasal inoculation the onset, extent, and severity of the prima ...19968801285
epidemiology of herpes simplex virus type 2 infections in a high-risk adolescent population.the seroprevalence of infection with type 2 herpes simplex virus (hsv-2) was determined in 135 adolescents detained in a juvenile detention facility. a total of 16% of enrollees were seropositive for hsv-2. age of onset of sexual intercourse, number of lifetime partners, frequency of condom use, and history of sexually transmitted diseases did not predict hsv-2 seropositivity.19968803729
evaluation of antiherpetic compounds using a gastric cancer cell line: pronounced activity of bvdu against herpes simplex virus replication.we developed a rapid and simple method for the screening of antiviral agents against herpes simplex virus (hsv) in a model of gastrointestinal herpetic infection in vitro. this method was based on inhibition of hsv-induced cytopathogenicity in gastric adenocarcinoma mkn-28 cells, as monitored by an mtt colorimetric assay. from the various compounds that were evaluated for their activity against hsv-1 and hsv-2, brivudine (bvdu) emerged as the most effective. when the 50% effective concentration ...19968805100
unique fold and active site in cytomegalovirus protease.human herpesviruses are responsible for a variety of diseases. they are divided into three subfamilies: alpha includes herpes simplex viruses (hsv-1 and hsv-2) and varicella-zoster virus (vzv); beta includes cytomegalovirus (cmv) and human herpesvirus-6 (hhv-6); and gamma includes epstein-barr virus (ebv). each virus encodes a serine protease that is essential for its replication and is a potential target for therapeutic intervention. human cmv is a ubiquitous opportunistic pathogen that can res ...19968805707
cellular uptake and biological effects of antisense oligodeoxynucleotide analogs targeted to herpes simplex virus.in this study, we synthesized antisense oligodeoxynucleotides (odns) with phosphodiester, phosphorothioate (s-odns), or methylphosphonate linkages complementary to the splicing acceptor site of immediate-early pre-mrna 5 of herpes simplex virus type 1 (hsv-1). the antiviral activity of each analog on cytopathic effect in cells infected with hsv-1 or hsv-2 was assessed and compared with the cellular uptake of the analog. we found that antisense s-odns showed the most potent antiherpetic activity, ...19968807060
nucleosides with a twist. can fixed forms of sugar ring pucker influence biological activity in nucleosides and oligonucleotides?the sugar moiety of nucleosides in solution is known to exist in a rapid dynamic equilibrium between extreme northern and southern conformations as defined in the pseudorotational cycle. in the present work, we describe how the bicyclo[3.1.0]hexane template fixes the ring pucker of 2'-deoxy-methanocarba-nucleosides 1-5 and 12 to values corresponding to either one of these two extreme conformations that are typical of nucleosides. the syntheses of the fixed northern conformers 1-5 were performed ...19968809162
subclinical shedding of hsv: its potential for reduction by antiviral therapy. 19968815678
seroepidemiology and control of genital herpes: the value of type specific antibodies to herpes simplex virus.herpes simplex virus (hsv) type 2 is the main cause of genital herpes infections. conventional serological techniques cannot discriminate between antibodies specific to hsv types 1 and 2, so these methods cannot be used in the seroepidemiological investigation of genital herpes infections. the discovery of type specific antigens in hsv-1 and hsv-2, most notably glycoprotein g (gg), has been successfully exploited to develop assays for the detection of type specific hsv antibody. the presence of ...19968820192
disseminated herpesvirus infection during pregnancy.a case of disseminated herpes simplex virus infection during pregnancy is reported, and 26 similar cases are reviewed. the present case was unusual in that it occurred in the 12th week of gestation, whereas all but one of the other cases occurred in the second or third trimester. this rare complication is generally preceded by a flu-like prodrome with or without oral or genital lesions. the clinical presentation is (1) encephalitis without hepatic involvement, (2) hepatitis with or without centr ...19968824966
inoculation herpes simplex virus infections in patients with aids: unusual appearance and location of lesions.two patients with aids developed protracted infection due to autoinoculation of herpes simplex virus in the great toe and the external ear, respectively, both unusual areas for inoculation. the appearances of the lesions were also unusual; severe hyperkeratosis was noted in both cases and a mass lesion in the external ear in one case. both patients' conditions responded to acyclovir, although one patient required amputation of a digit due to intractable pain. in each case, the diagnosis was dela ...19968824981
lack of detection of hsv dna in pbmcs and lymph nodes of hiv-infected persons. 19968825709
the relationship of human papillomavirus-related cervical tumors to cigarette smoking, oral contraceptive use, and prior herpes simplex virus type 2 infection.it has now been established that infection with human papillomavirus (hpv) is necessary for the development of most cervical cancers. hpv is not sufficient for the development of cancer. other exposures or host factors are necessary for cancer to occur. as part of an ongoing, population-based case-control study of invasive cervical cancer, we investigated the role of cigarette smoking, oral contraceptive (oc) use, and herpes simplex virus type 2 (hsv-2) as potential cofactors with hpv in the dev ...19968827359
acyclic nucleotide analogs derived from 8-azapurines: synthesis and antiviral activity.reaction of phosphoroorganic synthons with 8-azaadenine, 8-aza-2, 6-diaminopurine, and 8-azaguanine using cesium carbonate yielded regioisomeric 8-azapurine n7-, n8-, and n9-(2-(phosphonomethoxy)alkyl) derivatives. this reaction followed by deprotection afforded isomeric 2-(phosphonomethoxy)ethyl (pme), (s)-(3-hydroxy-2-(phosphonomethoxy)propyl) [(s)-hpmp], (s)-(3-flouro-2-(phosphonomethoxy)propyl) [(s)-fpmp], (s)-(2-(phosphonomethoxy)propyl) [(s)-pmp], and (r)-(2-(phosphonomethoxy)propyl) [(r)- ...19968831773
herpetic croup: two case reports and a review of the literature.croup is an acute infectious illness usually occurring in children; it is characterized by brassy cough and stridor. the main pathogens include mainly parainfluenza and influenza viruses. recently there have been reports of prolonged croup caused by the herpes simplex viruses. we report two cases of prolonged croup due to herpes simplex types 1 and 2. we also review and summarize the reported pediatric cases of herpetic croup.19968834994
a case of varicella-zoster myelopathy.early diagnosis of neurological complications of varicella-zoster virus (vzv) is important because of its treatability. we performed polymerase chain reaction (pcr) to detect vzv-dna from the cerebrospinal fluid (csf) of a patient with myelopathy.19968836311
the pharmacological profile of famciclovir.famciclovir is the well-absorbed oral form of penciclovir, a potent and selective antiviral agent, with activity against members of the herpesvirus family, including varicella-zoster virus (vzv), and herpes simplex virus-1 (hsv-1) and hsv-2. famciclovir is rapidly absorbed and converted to penciclovir. penciclovir has excellent bioavailability (77%) after oral administration of 500 mg of famciclovir. similar to acyclovir, famciclovir is converted by phosphorylation to its active metabolite, penc ...19968840412
a short-term plaque assay for antiviral drug research on herpes simplex virus type 2.in antiviral drug research, gelatinized growth medium cannot be used after infection to avoid the development of secondary plaques, because agar or other chemicals may interfere with the assessment of cytotoxic activity of antiviral compounds. in this study we evaluated quantitatively the different expression of cytopathic effects of herpes simplex virus type 2 (hsv-2) in vero cell cultures utilizing different periods of incubation after infection, and analysed the incidence of viral progeny par ...19968841042
in vitro study of a double infection by herpes simplex virus type 2 and chlamydia trachomatis.sexually transmitted diseases (stds) may recognize multiple etiological agents. among them, chlamydia trachomatis (ct) and herpes simplex virus type 2 (hsv-2) cause symptomatic, subclinical and asymptomatic infections of the urogenital tract which can lead to serious sequelae. in the present study the coinfection and superinfection by ct and hsv-2 in epithelial cultured cells from human cervix (hela 229) are described. a double infection, followed by the intracellular synthesis of chlamydial and ...19968841043
a facile synthesis of 4'-thio-arabinonucleosides as potential antiviral agents from d-glucose.as potential antiviral agents, 4'-thio-arabinonucleosides were synthesized. methyl 3-o-benzyl-xylo-furanoside, readily obtained from d-glucose, was converted to 1,4-anhydro-4-deoxy-4-thio-arabinitol. the protection of hydroxyl groups and the pummerer rearrangement, followed by lewis acid induced glycosylation afforded 4'-thio-arabinonucleosides. the compounds showed anti hsv-1 activity.19958841532
synthesis of carbocyclic oxetanocin analogs bearing fluorine and their antiviral activities.a new procedure to introduce the fluorine into the carbocycle of carbocyclic oxetanocin in a (c.oxt-a) was developed. the cyclobutanols 5 and 10, obtainable from the 2,3-di-o-benzoate 3, were condensed with 6-chloropurine using mitzunobu reaction to give the cyclobutyl nucleosides 6 and 11, respectively. addition of iodine fluoride to compound 6 afforded [(1r*,2s*,3r*)-isomer 7 as a sole addition product, which was converted to 1. this compound (1) exhibited a broad spectrum of antiviral activit ...19958841601
multicentre clinical trial with herpes simplex virus vaccine in recurrent herpes infection.the aim of this work was to confirm our preliminary clinical and immunological evaluation of the protective effects of a herpes simplex virus (hsv) vaccine derived from killed virus in the treatment of relapsing facial or genital herpes simplex infection. a total of 142 patients were treated with the hsv vaccine and a control group of 50 were treated with intermittent oral acyclovir (acv). the vaccine reduced annual active disease days in vaccinees to 11.59 (+/- 15.3) after treatment (65.11 +/- ...19958845402
the cell-coded polypeptide u90 increased by herpes simplex virus type 2 infection induces fos and dna synthesis.lytic infection with herpes simplex virus type 2 (hsv-2) induces synthesis of a cell-coded protein of molecular mass 90 kda, termed u90. u90, whose expression is specific in tumour cells is, in addition, excreted from he cell. to determine if the function of u90 could be advantageous for the virus the protein was purified from the medium of hsv-2 infected cells, shown to be similar to the internalized form and its effect on cell growth studied. addition of u90 to quiescent fibroblast cells stimu ...19958847520
sexually transmitted diseases in australia: a decade of change. epidemiology and surveillance.survival data in the last decade for sexually transmitted diseases (stds) other than human immunodeficiency virus (hiv) are uneven across the states/territories. the incidence of gonorrhoea decreased by more than 80%, but at different times in different patient groups, different states, and different anatomical sites. there was a resurgence of rectal gonorrhoea in homosexual men in 1989-1991. resistance to penicillin steadily increased, and partial resistance to quinolones has emerged. there was ...19958849191
recent advances in genital herpes.the majority of transmissions occur as a consequence of inapparent infection in the source contact, as asymptomatic viral excretion in individuals with recurrent infection. the development of type specific serological assays has allowed for a more accurate determination of herpes simplex virus (hsv) 2 prevalence and has revealed that the prevalence of hsv 2 in sexually transmitted disease clinic attenders varies from 8%-83%, in female prostitutes from 75%-96% and in antenatal clinic attenders fr ...19958849193
comparison of effects of famciclovir and valaciclovir on pathogenesis of herpes simplex virus type 2 in a murine infection model.the effects of famciclovir (fcv) and valaciclovir (vacv) were compared in a cutaneous infection model for herpes simplex virus type 2 (hsv-2). the compounds were administered orally from day 1 to day 5 postinfection. both compounds reduced local inflammation and virus replication in the skin. fcv markedly reduced mortality and virus replication in the nervous system. on the cessation of therapy after 5 days, when the levels of infectious virus in the tissues were reduced to below the level of de ...19968849238
synthesis and antiviral activity of 5-substituted (2's)-2'-deoxy-2'-c-methylcytidines and -uridines.synthesis of several 5-substituted (2's)-2'-deoxy-2'-c-methylcytidines (8) and -uridines (6, 11) has been accomplished using radical deoxygenation of the 2'-tert-alcohols via their methyl oxalyl esters as a key reaction. anti-herpes simplex virus type-1 and -2, and anti-varicella-zoster virus activities of the newly synthesized nucleosides were evaluated. among them, the 5-iodouracil derivative 6e showed the most potent activity against herpes simplex virus type-1, with an ec50 of 0.14 microgram ...19968851469
administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase i/ii trial.neonatal herpes simplex virus (hsv) infections limited to the skin, eyes and mouth (sem) can result in neurologic impairment. a direct correlation exists between the development of neurologic deficits and the frequency of cutaneous hsv recurrences. thus, the national institutes of allergy and infectious diseases collaborative antiviral study group conducted a phase i/ii trial of oral acyclovir therapy for the suppression of cutaneous recurrences after sem disease in 26 neonates.19968852914
polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in hiv-infected patients.to assess the diagnostic reliability of polymerase chain reaction (pcr) on cerebrospinal fluid (csf) for virus-associated opportunistic diseases of the central nervous system (cns) in hiv-infected patients.19968853727
genital herpes simplex virus infection in females in ibadan nigeria.in a study of female patients attending the sexually transmitted diseases clinic of the university college hospital ibadan, nigeria, herpes simplex virus was isolated from the cervix of 5 of 117 patients, a prevalence rate of 4.3%. two (1.7%) of these patients had hsv in the vagina. the viruses were identified by culture in hep-2 cell line, chloroform sensitivity test, complement fixation test and indirect immuno-fluorescent antibody technique. only one (20%) of the five patients has hsv-1 in th ...19968855674
cause of oral ulcers in hiv-infected patients: a study of 19 cases.to study the cause and clinical aspects of oral ulcers in hiv-infected patients.19968863306
inhibition of three alphaherpesviruses (herpes simplex 1 and 2 and pseudorabies virus) by heparin, heparan and other sulfated polyelectrolytes.the first step of the herpes virus infection is the attachment to heparan sulfate molecules on the cellular membrane. in order to improve the characterization of this phenomenon, we compared the inhibitory effect of six sulfated polyelectrolytes (pe): heparin, heparan, low molecular weight heparin, chondroitin, dextran and protamine on plaque formation by pseudorabies virus (prv) were compared. the pe with the highest antiherpetic effect was heparin, followed by dextran sulfate. heparan sulfate, ...19968867366
herpes simplex virus blocks intracellular transport of hla-g in placentally derived human cells.spontaneous fetal loss is associated with herpes simplex virus (hsv) infection as deduced from epidemiologic data. to date, the underlying mechanisms remain to be elucidated, but an immune component is suspected. hla-g is a class i mhc molecule selectively expressed on extravillous cytotrophoblast; this cell type does not express conventional hla-a or -b, whereas expression of novel hla-c-like products has been reported. while its function remains unclear, a role for hla-g in silencing nk cells ...19968871634
induction of a protective immune response by mucosal vaccination with a disc hsv-1 vaccine.the vaccine potential of a genetically disabled herpes simplex virus type 1 virus (disc hsv-1) was investigated in the guinea pig model of intravaginal (i.vag.) hsv-2 infection. three mucosal vaccination routes, i.vag., intranasal (i.n.) and oral, were compared for their ability to protect guinea pigs from challenge with wild-type hsv-2. each was effective, particularly the i.n. route, which almost completely abolished primary disease. this was accompanied by significantly lower challenge virus ...19968873393
effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract.this study demonstrates that the levels of gb-specific igg and iga in vaginal washes of mice immunized intranasally (i.n.) with a recombinant adenovirus vector expressing herpes simplex virus (hsv) glycoprotein b (adgb8) vary inversely with each other and are dependent on the stage of the estrous cycle. anti-gb iga titers in vaginal washes were significantly higher during estrus than diestrus or proestrus, whereas specific igg titers were significantly higher during diestrus than estrus. this wa ...19968874509
immunization with dna vaccines encoding glycoprotein d or glycoprotein b, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease.dna vaccines expressing herpes simplex virus type 2 (hsv-2) full-length glycoprotein d (gd), or a truncated form of hsv-2 glycoprotein b (gb) were evaluated for protective efficacy in two experimental models of hsv-2 infection. intramuscular (i.m.) injection of mice showed that each construction induced neutralizing serum antibodies and protected the mice from lethal hsv-2 infection. dose-titration studies showed that low doses (< or = 1 microgram) of either dna construction induced protective i ...19968876149
evaluation of a new general primer pair for rapid detection and differentiation of hsv-1, hsv-2, and vzv by polymerase chain reaction.the polymerase chain reaction (pcr) enables rapid and sensitive detection of vzv and hsv dna and its efficiency depends mainly on the choice of the primers. primers should hybridize to conserved dna sequences within the viral genomes in order to avoid unreliable amplification due to dna sequence variation between different strains. the aim of the study was to design and to evaluate a general primer pair which permits fast and reliable detection of hsv and vzv. the genes ul 15 of hsv and ul 42 of ...19968877759
enhancement of hsv-dna infectivity, in vero and rs cells, by a modified calcium-phosphate transfection technique.infectivity of herpes simplex virus (hsv) dna was assessed by employing the calcium-phosphate transfection technique described by chen and okayama, originally applied to increase the efficiency of plasmid transfection by n, n-bis (2-hydroxyethyl)-2-aminoethane sulfonic acid (bes). the experimental conditions and efficiency of this transfection procedure were evaluated comparing the viral progeny titers obtained by the chen and okayama transfection method using dna from wild-type strains of hsv-1 ...19968879137
escherichia coli expressed herpes simplex virus gg1 and gg2 proteins in elisa and immunoblotting assays.the type 1 and type 2 glycoprotein g (gg1 and gg2) of herpes simplex virus (hsv) were expressed in escherichia coli as fusion proteins with the maltose binding protein (mbp) using the pmal-c2 expression vector. the mbp-gg1 fusion protein contains all but the four amino acids from the amino-terminus of gg1, whereas the mbp-gg2 fusion protein was missing the first 30 amino acids that comprise the signal peptide of the protein. the diagnostic value of these antigens was examined by two methods: (1) ...19958880385
viral serologies in patients with chronic fatigue and chronic fatigue syndrome.chronic fatigue syndrome (cfs) is an illness characterized by disabling fatigue associated with complaints of fevers, sore throat, myalgia, lymphadenopathy, sleep disturbances, neurocognitive difficulties, and depression. a striking feature of cfs is its sudden onset following an acute, presumably viral, illness and the subsequent recurrent "flu-like" symptoms. it has been speculated that both cfs and debilitating chronic fatigue (cf) that does not meet strict criteria for cfs may be the direct ...19968890037
suitability and clinical application of a multiplex nested pcr assay for the diagnosis of herpes simplex virus infections.a novel multiplex nested polymerase chain reaction (pcr) assay was designed and evaluated for routine diagnosis of herpes simplex virus (hsv) infections in patients with either putative hsv infection of the central nervous system or suspected hsv keratitis. single-tube amplification of hsv type 1 (hsv-1) or type 2 (hsv-2) dna extracted from cerebrospinal fluid (csf) or from keratectomy specimens was followed by differentiation of the virus type-specific pcr products either by agarose gel analysi ...19968890044
the role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. the eu concerted action on virus meningitis and encephalitis.as effective therapies for the treatment of herpes simplex encephalitis (hse) have become available, the virology laboratory has acquired a role of primary importance in the early diagnosis and clinical management of this condition. several studies have shown that the polymerase chain reaction (pcr) of csf for the detection of herpes simplex virus type 1 (hsv-1) or type 2 (hsv-2) dna provides a reliable method for determining an aetiological diagnosis of hse. the use of pcr in combination with t ...19968890768
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