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PubMed1999

Accumulation of specific RNAs encoding transcriptional factors and stress response proteins against a background of severe depletion of cellular RNAs in cells infected with herpes simplex virus 1.

Herpes simplex virus 1 encodes several functions to preclude the shutoff of host response to infection, including degradation of mRNA immediately after infection. To determine whether any cellular mRNAs accumulate in infected cells against a background of severe loss of host RNA, we hybridized cDNAs derived from three different cell lines infected with wild type and a mutant virus to a DNA array containing probes for 588 human genes representing different functional groups. The results were that (i) infected cells accumulated at levels above those of mock-infected cells, a small number of transcripts representing transcriptional factors that could regulate gene expression both positively and negatively, and one stress response protein (GADD45), (ii) the amount and nature of the accumulated transcripts showed limited variability depending on the cell and virus, and (iii) at least some of the proteins encoded by the accumulated transcripts could benefit either the virus or the host.

Cell Line↗
PubMed1997

Anti-interleukin-6 antibodies inhibit herpes simplex virus reactivation.

Herpes simplex viruses (HSVs) infect epithelial cells, become localized in neurons, and can reactivate in response to a variety of stimuli, including ultraviolet light and hyperthermia. The sequence of gene activation during viral replication is known, but the molecular linkage between exogenous stimuli and HSV reactivation has not been determined. It was hypothesized that interleukin (IL)-6 acts as a signal between exogenous stimuli and neurons, stimulating HSV reactivation from latency. Mouse corneas were infected with HSV-1, and ocular reactivation was induced 5-7 weeks later by thermal stress or corneal exposure to ultraviolet light. Anti-IL-6 monoclonal antibodies were administered to the latently infected mice 8-12 h before the reactivation stimulus. Treatment with anti-IL-6 antibodies resulted in significantly lower frequencies of ocular reactivation compared with those in mice treated with a control immunoglobulin. These results support the hypothesis that IL-6 plays a role in HSV reactivation from latency.

Animals↗
PubMed2001

Efficacy of polyclonal antibodies for treatment of ocular herpes simplex infection.

PURPOSE: Herpes simplex virus (HSV) can cause corneal infections in humans and lead to permanent scarring, loss of vision, and blindness. Current treatment of epithelial HSV keratitis consists of using antiviral DNA analogs. In this study, we used in vitro and in vivo models to evaluate the efficacy of six polyclonal antibodies to HSV recombinant surface glycoprotein D in treating ocular epithelial HSV. METHODS: Confluent cultures of African Green monkey kidney fibroblasts (Vero cells) and normal 3-to 5-lb female New Zealand White rabbits were infected with HSV type 1, strain RE. In vitro virucidal and antiviral assays were performed, and the best of the compounds was chosen for the in vivo stage. Animals were carefully monitored until day 5 after HSV-1 inoculation, then arbitrarily divided into groups receiving, for 14 days, varying doses of: polyclonal antibodies four times a day, polyclonal antibodies three times a day, trifluorothymidine (current treatment of choice and the positive control) nine times a day, or 0.9% physiologic saline nine times a day. The animals were followed up in a masked fashion and carefully monitored for severity and resolution of the HSV infection by biomicroscopy (slit lamp) examination and viral cultures using standardized plaque assays. RESULTS: All six of the compounds tested were effective in vitro, but one compound in particular, SP-510-50, was superior. It was used for the in vivo testing and showed antiviral efficacy in a dose-dependent manner, and at dosing four times a day, it was of comparable efficacy to trifluorothymidine (nine times a day). CONCLUSIONS: We conclude that polyclonal antibodies to glycoprotein D appear to be effective antiviral agents in vitro and in vivo in a rabbit model of HSV-1 keratitis and show promise as a new antiviral treatment for ophthalmic use.

Animals↗
PubMed1989

Latent infections in spinal ganglia with thymidine kinase-deficient herpes simplex virus.

A herpes simplex virus type 1 variant [C239(TK-)] harboring a deletion in the thymidine kinase (TK) gene was assessed for capacity to establish latent infections. Outbred Swiss Webster mice were inoculated on both hind footpads, and numbers of neurons expressing latency-associated transcript and amounts of viral DNA in latently infected lumbosacral spinal ganglia were scored. C239(TK-) established levels of latent infection that were only slightly lower than those found for either a TK rescued variant of this agent or the parent wild-type KOS. However, in contrast to the TK+ viruses, C239(TK-) could not be reactivated when spinal ganglia were cultured in vitro. The results presented show that expression of the viral TK gene plays no major role in establishment of the latent state but that it functions during reactivation of latent virus from explanted ganglia maintained in vitro.

Animals↗
PubMed1989

Identification of the latency-associated transcript promoter by expression of rabbit beta-globin mRNA in mouse sensory nerve ganglia latently infected with a recombinant herpes simplex virus.

The herpes simplex virus type 1 latency-associated transcript (LAT) is expressed as a major species in latently infected mouse neurons. Previous sequence analysis revealed no obvious promoter elements near the 5' end of the LAT, but a TATA box and other potential promoter elements were found 700 base pairs upstream. A recombinant virus in which the rabbit beta-globin gene was inserted immediately downstream of the TATA box expressed globin mRNA and did not express the LAT. A second recombinant virus, in which this TATA box was removed, was negative for LAT expression in a latent infection. The location of the LAT promoter suggested that RNA upstream of the LAT was synthesized and degraded during latent-phase transcription. Low levels of this RNA were observed by in situ hybridization. In other experiments, RNA from a productive infection was used to detect a transcript extending from the LAT promoter to a polyadenylation signal approximately 8.5 kilobase downstream. These data suggest that the LAT may be processed from a larger transcription unit which begins distal to the TATA box 700 base pairs upstream of the LAT and extends to a polyadenylation signal almost 5 kilobases downstream of the 3' end of the LAT.

Animals↗
PubMed1993

Incorporation of CD4 into virions by a recombinant herpes simplex virus.

Two herpes simplex virus type 1 (HSV-1) recombinants were constructed by inserting the human CD4 gene into the HSV-1 genome between the gC promoter and the gC structural gene. These viruses, designated K delta T/CD4 and K082/CD4, synthesized a significant quantity of CD4. CD4 was expressed on the surface of infected cells at levels substantially higher than on the surface of HUT78 cells, a CD4+ cell line. Most significantly, a small but detectable quantity of CD4 was incorporated into virions produced by the recombinant viruses. This was demonstrated both by immunoprecipitation of CD4 from purified virions and by neutralization of the recombinant virions by OKT4 and complement. These results suggest that specific virion incorporation signals are not strictly required for inclusion of glycoproteins into HSV-1 virions. It may be possible to utilize this ability to alter the host range or tissue specificity of HSV-1.

Animals↗
PubMed1994

Cell-free assembly of the herpes simplex virus capsid.

Herpes simplex virus type 1 (HSV-1) capsids were found to assemble spontaneously in a cell-free system consisting of extracts prepared from insect cells that had been infected with recombinant baculoviruses coding for HSV-1 capsid proteins. The capsids formed in this system resembled native HSV-1 capsids in morphology as judged by electron microscopy, in sedimentation rate on sucrose density gradients, in protein composition, and in their ability to react with antibodies specific for the HSV-1 major capsid protein, VP5. Optimal capsid assembly required the presence of extracts containing capsid proteins VP5, VP19, VP23, VP22a, and the maturational protease (product of the UL26 gene). Assembly was more efficient at 27 degrees C than at 4 degrees C. The availability of a cell-free assay for HSV-1 capsid formation will be of help in identifying the morphogenetic steps that occur during capsid assembly in vivo and in evaluating candidate antiherpes therapeutics directed at capsid assembly.

Capsid↗
PubMed1995

Glycoproteins E and I facilitate neuron-to-neuron spread of herpes simplex virus.

Two herpes simplex virus (HSV) glycoproteins E and I (gE and gI) form a heterooligomer which acts as an Fc receptor and also facilitates cell-to-cell spread of virus in epithelial tissues and between certain cultured cells. By contrast, gE-gI is not required for infection of cells by extracellular virus. HSV glycoproteins gD and gJ are encoded by neighboring genes, and gD is required for both virus entry into cells and cell-to-cell spread, whereas gJ has not been shown to influence these processes. Since HSV infects neurons and apparently spreads across synaptic junctions, it was of interest to determine whether gD, gE, gI and gJ are also important for interneuronal transfer of virus. We tested the roles of these glycoproteins in neuron-to-neuron transmission of HSV type 1 (HSV-1) by injecting mutant viruses unable to express these glycoproteins into the vitreous body of the rat eye. The spread of virus infection was measured in neuron-rich layers of the retina and in the major retinorecipient areas of the brain. Wild-type HSV-1 and a gJ- mutant spread rapidly between synaptically linked retinal neurons and efficiently infected major retinorecipient areas of the brain. gD mutants, derived from complementing cells, infected only a few neurons and did not spread in the retina or brain. Mutants unable to express gE or gI were markedly restricted in their ability to spread within the retina, produced 10-fold-less virus in the retina, and spread inefficiently to the brain. Furthermore, when compared with wild-type HSV-1, gE- and gI- mutants spread inefficiently from cell to cell in cultures of neurons derived from rat trigeminal ganglia. Together, our results suggest that the gE-gI heterooligomer is required for efficient neuron-to-neuron transmission through synaptically linked neuronal pathways.

Animals↗
PubMed2003

Specific association of glycoprotein B with lipid rafts during herpes simplex virus entry.

Herpes simplex virus (HSV) entry requires the interaction of glycoprotein D (gD) with a cellular receptor such as herpesvirus entry mediator (HVEM or HveA) or nectin-1 (HveC). However, the fusion mechanism is still not understood. Since cholesterol-enriched cell membrane lipid rafts are involved in the entry of other enveloped viruses such as human immunodeficiency virus and Ebola virus, we tested whether HSV entry proceeds similarly. Vero cells and cells expressing either HVEM or nectin-1 were treated with cholesterol-sequestering drugs such as methyl-beta-cyclodextrin or nystatin and then exposed to virus. In all cases, virus entry was inhibited in a dose-dependent manner, and the inhibitory effect was fully reversible by replenishment of cholesterol. To examine the association of HVEM and nectin-1 with lipid rafts, we analyzed whether they partitioned into nonionic detergent-insoluble glycolipid-enriched membranes (DIG). There was no constitutive association of either receptor with DIG. Binding of soluble gD or virus to cells did not result in association of nectin-1 with the raft-containing fractions. However, during infection, a fraction of gB but not gC, gD, or gH associated with DIG. Similarly, when cells were incubated with truncated soluble glycoproteins, soluble gB but not gC was found associated with DIG. Together, these data favor a model in which HSV uses gB to rapidly mobilize lipid rafts that may serve as a platform for entry and cell signaling. It also suggests that gB may interact with a cellular molecule associated with lipid rafts.

Animals↗
PubMed2006

Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Deltagamma(1)34.5 mutants of herpes simplex virus 1.

Herpes simplex virus mutants lacking the gamma(1)34.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Deltagamma(1)34.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Deltagamma(1)34.5 mutant viruses to replicate in and destroy tumor cells.

Animals↗
PubMed2001

Multiple applications for replication-defective herpes simplex virus vectors.

Herpes simplex virus (HSV) is a neurotropic DNA virus. The viral genome is large (152 kb), and many genes are dispensable for viral function, allowing insertion of multiple or large transgene expression cassettes. The virus life cycle includes a latent phase, during which the viral genome remains as a stable episomal element within neuronal nuclei for the lifetime of the host, without disturbing normal function. We have exploited these features of HSV to construct a series of nonpathogenic gene therapy vectors that efficiently deliver therapeutic and experimental transgenes to neural and non-neural tissue. Importantly, transgene expression may be sustained long term; reporter gene expression has been demonstrated for over a year in the nervous system. This article discusses the generation of replication-defective HSV vectors and reviews recent studies investigating their use in several animal models of human disease. We have demonstrated correction or prevention of a number of important neurological phenotypes, including neurodegeneration, chronic pain, peripheral neuropathy, and malignancy. In addition, HSV-mediated transduction of non-neurological tissues allows their use as depot sites for synthesis of circulating and locally acting secreted proteins. New applications for this vector system include the genetic modification of stem cell populations; this may become an important means to direct cellular differentiation or deliver therapeutic genes systemically. Replication-defective HSV vectors are an effective and flexible vehicle for the delivery of transgenes to numerous tissues, with multiple applications.

Genes, Reporter↗
PubMed1987

Histopathologic characteristics of two forms of experimental herpes simplex virus retinitis.

Herpes simplex virus type 1 (HSV-1) inoculated intracamerally into one anterior chamber of a BALB/c mouse produces retinitis in the uninoculated contralateral eye within 7 to 10 days while the retina of the inoculated eye is spared. In sharp contrast, animals receiving HSV type 2 (HSV-2) by the anterior chamber route develop a dramatic retinitis in the inoculated eye by day 7 postinoculation while the retina of the contralateral eye remains uninvolved. Histopathologic examination of retinal destruction in the HSV-2-infected ipsilateral eye revealed features which were distinct from those observed in the contralateral eye of HSV-1-infected animals. Whereas HSV-1 produced a rapid, explosive, retinitis which led to destruction of all cell layers of the contralateral retina, HSV-2 induced a retinitis in the ipsilateral eye that was more gradual in onset. Ipsilateral HSV-2 retinitis was characterized initially by disruption of the ganglion and inner nuclear layers which progressed by day 10 to 14 to complete replacement of the retina by a fibrocellular scar. These changes were dominated by a vigorous mononuclear cell infiltrate, a feature not observed in the HSV-1-infected contralateral retinitis. These results suggest that experimental retinitides produced by HSV-1 and HSV-2 are of diverse pathogenesis.

Animals↗
PubMed1981

The use of Staphylococcus aureus rich in protein A in the detection of herpes simplex virus antigens.

Herpes simplex virus (HSV) type 1 antigens were detected in infected human embryonic lung cells with the aid of specific antiserum and Staphylococcus aureus rich in protein A. When such staphylococci carrying specific anti-HSV IgG on their surface were interacted with various suspension of virus, a reduction in the initial virus titre of about 65% was obtained. However, no direct coagglutination was observed between cell-free supernatants of HSV or HSV-infected cells and sensitized staphylococci. When monolayers or suspended cells infected with the virus were treated with dilutions of specific anti-HSV antiserum followed by non-sensitized staphylococci (indirect method), an "aureola" of the bacteria was detected around the cells expressing the viral antigens. A similar picture was observed when infected cells were interacted directly with sensitized staphylococci. Viral antigens were detected already 12 hours post infection, well before the appearance of cytopathic effect. The sensitivity of the indirect method was found to be higher than that of the direct one and dependent on the multiplicity of infection and the serum dilution used. The method is proposed as a rapid means of identifying viral antigens in diagnostic and experimental virology.

Antigens, Viral↗
PubMed1994

Herpes simplex virus infections of women and their offspring: implications for a developed society.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.

Antiviral Agents↗
PubMed2000

[Immunogenic activity of temperature sensitive mutation of herpes simplex virus type-1 in mono- and polyvalent conditions with different attenuated strains of virus. I. Analysis of humoral immunity induced by mutant temperature sensitive herpes simplex virus type-1 in monovalent systems].

The aim of the present study was the analysis of the immunogenic activity of temperature sensitive mutant of HSV-1 with significantly decreased pathogenicity for mice. The stability of immunogenic potency was also tested. The level of antibody-mediated response in guinea pigs after two doses of mutant ts HSV-1 or native strain was compared. Antibodies to HSV were measured using ELISA and CFM. Seroconversion rates in tested groups were high, from 80% to 100%. The level of antibody response at 4 week after inoculation measured by ELISA and CFM showed no significant differences between 4 passages of mutant ts HSV-1. Significant higher increase of antibodies level after two doses of viruses was observed for mutant ts HSV-1 as compared to native strain, both in ELISA and CFM.

Animals↗
PubMed1983

Enzyme-linked immunosorbent assay for detection and typing of herpes simplex virus.

An enzyme-linked immunosorbent assay for herpes simplex virus was tested using commercially available peroxidase-conjugated and unconjugated rabbit antibodies to herpes simplex virus type 1 and type 2 (DAKO immunoglobulins A/S, Copenhagen, Denmark). One hundred and thirty-seven clinical specimens from vesicles and superficial cutaneous lesions were tested and the results compared with virus isolation. In addition 210 herpes simplex virus isolates were typed. Forty-four specimens yielded herpes simplex virus both in the enzyme-linked immunosorbent assay and in tissue culture and 79 were negative in both tests. Fourteen were positive in isolation but negative in the enzyme-linked immunosorbent assay. Seventy-three isolates were typed as herpes simplex virus type 1 and 137 as herpes simplex virus type 2. The enzyme-linked immunosorbent assay was found to be rapid and easy to perform but less sensitive than conventional isolation in routine diagnostic work. For typing of isolates it was found to be a useful method for distinguishing herpes simplex virus type 1 and type 2.

Animals↗
PubMed1990

Detection of herpes simplex virus by the Kodak SureCell Herpes Test.

The Kodak SureCell Herpes Test Kit (SC-HSV) was evaluated in a high-risk sexually transmitted disease clinic population. A total of 97 lesion specimens (from 94 patients) were tested for the presence of herpes simplex virus by SC-HSV and by spin-amplified tissue culture confirmed by an enzyme immunoassay. The overall sensitivity of SC-HSV compared with that of spin-amplified tissue culture-enzyme immunoassay was 81.1%; the specificity was 100%. For vesicular lesions only, SC-HSV sensitivity was 100%; for nonvesicular lesions, sensitivity was 75.6%, SC-HSV was rapid (less than 15 min) and very easy to perform.

Antibodies, Monoclonal↗
PubMed1996

High frequency of CD8+ cytotoxic T-lymphocyte precursors specific for herpes simplex viruses in persons with genital herpes.

Herpes simplex virus (HSV)-specific CD8+ cytotoxic T lymphocytes (CTL) have rarely been detected in humans, presumably because of virus-induced mechanisms that downregulate major histocompatibility complex class I expression. We have developed a method that has allowed us to consistently demonstrate HSV-specific CD8+ precursor CTL (pCTL) from HSV type 1- and 2-seropositive persons. Major histocompatibility complex-restricted HSV-specific CD8+ pCTL were found in 10 consecutively tested HSV type 1- and 2-seropositive subjects at frequencies ranging from 1 in 21,000 to 1 in 300 (median, 1 in 6,000) versus a pCTL frequency of 1 in 100,000 in HSV-seronegative donors. These results suggest that CD8+ CTL are important effector cells in resolving HSV lesions.

Herpes Genitalis↗