Resistance to vaginal or systemic infection with herpes simplex virus type 2

Summary Mortality due to vaginal or intravenous infection of female BALB/c mice with herpes simplex virus type 2 (HSV-2) was significantly reduced by treatment of mice with the immunomodulator pyran. Following intravaginal inoculation with virus, the incidence of vaginal infection and titers of virus present in the vaginal secretions were significantly reduced in pyran treated as compared with control mice. Vaginal infection did not elicit neutralizing antibody activity in either untreated or pyran treated mice. Intravenous HSV-2 infection did elicit virus specific humoral and delayed type hypersensitivity responses. However, pyran treatment markedly reduced the incidence of these immune responses as compared with those in control intravenously infected mice. Moreover, mice surviving the initial vaginal or intravenous infection with HSV-2 were resistant to subsequent rechallenge by the same route. Pyran treatment did not enhance resistance to vaginal rechallenge, while pyran treated mice were not resistant to intravenous rechallenge. Thus, the antiviral protection mediated by pyran does not appear to involve enhancement of specific humoral or cellular immune responses. Nonspecific host mediated resistance may be involved in the protective effect of the immunomodulator, as suggested by the ability of pyran activated peritoneal cells to inhibit HSV-2 growthin vitro and to transfer resistance to recipient mice challenged with the virus.With 1 Figure     

Neutralising antibody in mice with primary and recurrent herpes simplex virus infection

Summary Neutralising antibody was studied in mice infected in the ear with herpes simplex virus type 1. Antibody was detected six days after infection and after one month it had reached titres which subsequently varied little. Geometric group mean titres were doubled by reinoculation of virus whereas recurrent disease induced by trauma did not change them (although titres did change in some individual animals).Mean titres in mice which had had unequivocal signs of primary disease were twice as high as in those which had not, and the frequency of recurrent disease in response to trauma in the former animals was greater than in the latter. A reduction in the frequency of induced recurrent disease was seen if the application of trauma was delayed for some time after the establishment of latency.Hyperimmunisation increased mean titres tenfold. If given soon after primary infection it reduced the frequency of induced recurrent disease but if its administration was delayed then the frequency was increased.     

Resistance of human blood monocytes to infection with herpes simplex virus

Human blood monocytes isolated by centrifugal elutriation were resistant to infection with herpes simplex virus type 1 (HSV). In vitro cultivation for several days resulted in a stepwise increase of virus yield. Similar amounts of virus absorbed to fresh and cultured monocytes. No viral DNA was associated with the nuclear fraction of freshly isolated monocytes early after infection indicating that early steps of virus infection were already inhibited in resistant cells. This argues against HSV induced interferon (IFN) being a major mediator of resistance. Culturing the cells for some hours was sufficient to overcome the early block. However, as revealed by virus yield assays, monocytes after 1 day of cultivation were not as susceptible as cells after 6 days of cultivation. Viral sequences could be demonstrated in the nuclei of freshly isolated monocytes after treatment with the fusion-promoting agent polyethylene glycol. Under these conditions no DNA replication occurred, indicating that overcoming the block of viral DNA entry into the nucleus was not sufficient to break resistance of the cells. Thus, the results show that several mechanisms are involved in the primary resistance of human blood monocytes to HSV.     

Cell-mediated immunity in mice with primary,secondary and latent herpes simplex virus infection

Summary Cell mediated immunity was studied by a cytopathic effect inhibition assay in mice infected in the ear with herpes simplex virus type 1 (HSV 1). Activity appeared rapidly, reaching a high level 6 days after primary infection. It had fallen 10 days after infection and was undetectable during latency, 3–5 weeks after infection. The activity reappeared even more rapidly and strongly after reinoculation with the virus, but stimuli designed to induce recurrent disease did not induce clinical disease in the animals and no activity was detected in them.The activity, which was specific for HSV, was shown to be mediated by T-lymphocytes.With 1 Figure     

Experimental infection of inbred mice with herpes simplex virus

Summary Inbred mouse strains differ in susceptibility to infection with herpes simplex virus type 1 or type 2 (HSV-1, HSV-2). In this study interferon production was tested in the peritoneal exudate of mice after intraperitoneal (i.p.) injection of HSV-1 or HSV-2. In HSV-resistant mice (C57BL/6, C3H/HeJ) high titers of interferon were already present 2 to 4 hours after injection. In comparison, less resistant mice (DBA/2, AKR) lacked this early response. There was no correlation between interferon titers and resistance at post-infection times later than twelve hours. At twelve hours, however, high titers of HSV were detected in the peritoneum of DBA/2 mice and significantly lower titers in C57BL/6 mice. In a comparative analysis of eight different inbred mouse strains, again early (2 to 4 hours) interferon production was correlated to resistance. In assays of HSV-stimulated early (24 hours) NK cell responses not only the good interferon producer strains but also one of the less resistant low interferon producers (BALB/c) showed significant cytotoxic activities. Conversely, SJL mice that are very low in HSV-induced NK cell activity are resistant and show high early interferon responses at the local site.With 2 Figures     

Pathogenesis of genital herpes simplex virus infection in mice

Experiments in the mouse model of herpes simplex virus (HSV) infection involving the intact genital mucous membranes as inoculation site yielded the following results. In untreated mice the extent of latency was correlated with the degree of peripheral virus replication. This correlation could not be observed when the course of infection was interrupted by chemotherapy, interferon, or passive immunization. Acyclovir had little effect on peripheral virus multiplication, but markedly reduced latent ganglionic infection. As acute ganglionic infection and virus concentration in the spinal nerves were already reduced, acyclovir is assumed to inhibit either virus penetration into the nerve endings or virus replication in the ganglia. Interferon apparently has an active role in the elimination of virus infected cells from the ganglia, as its effect was restricted to a reduced rate of latency and of lethality. Passive immunization with antiserum led to similar results as ACV-treatment. While lacking a pronounced effect on virus replication in the mucous membranes, specific antibody was found to influence both virus elimination from the ganglia, and conversion from productive to latent ganglionic infection. Immune lymphocytes proved to be the only agent capable of suppressing peripheral infection, thereby inhibiting the neural spread of the virus. These results suggest that the decrease in latency may result from modulations occurring at different stages in the course of infection.Supported by Deutsche Forschungsgemeinschaft Schn 174/6-2     

An unusual bipolar primary herpes simplex virus 1 infection

We describe an atypical primary HSV 1 genital infection with bilateral palmar involvement. Two routes of dissemination of HSV are discussed, self-inoculation and blood dissemination. This case highlights the role of HSV 1 in extragenital pustules in the context of sexually transmitted diseases.     

Pathogenesis of genital herpes simplex virus infection in mice

This study was undertaken to establish the role of virulence of various herpes simplex virus (HSV) strains in the course of infection when applying the virus to the non-injured mucous membranes of mice.Wild-type HSV-type 1 (HSV-1) strains with marked differences in their neurovirulence following intracerebral inoculation showed minor differences in virulence after vaginal inoculation, but essentially their neurovirulence in cerebral infection corresponded to their virulence on the mucous membranes.In comparison with the wild-types, however, there were pronounced differences among syn- and TK^–-mutants of HSV-1 and HSV-2 in the degree of virulence at different sites in the course of virus infection. Whereas syn-mutants proved avirulent on the mucous membranes but not in neural tissues, TK^–-mutants were avirulent both on mucous membranes and in neural tissues.Ts-mutants of HSV-2 were not found to establish themselves when administered to the non-injured mucous membranes, nor did they induce neutralizing antibodies, but a later challenge with the wild-type virus at the same site lead only to an attenuated course of infection.Supported by the Deutsche Forschungsgemeinschaft Schn 174/6-2     

Interleukin-3 protects mice from acute herpes simplex virus infection.

Evidence presented here from kinetic studies of interleukin-3 (IL-3) production by spleen cells from adult mice infected subcutaneously with HSV-1 and stimulated with virus antigen in vitro shows that high levels of IL-3 were produced at the onset of the animal's recovery from the disease state. Injections of anti-IL-3 antibody into HSV-1-infected mice resulted in exacerbation of the disease. Primary mouse embryonic head cells grown in the presence of murine IL-3, when infected with HSV-1, showed a 1000-fold decrease in virus titre compared with untreated control cells. This inhibiting effect was reversed by anti-IL-3 and anti-IFN-alpha, beta and gamma antibodies. These data suggest that IL-3 plays a host-protective role against HSV infection and it does so probably by inducing brain cells to produce interferons which then inhibit virus replication.     

Vaginal formulations of carrageenan protect mice from herpes simplex virus infection.

The observations from the present study indicate that vaginal formulations of the sulfated polysaccharide carrageenan are highly effective in protecting mice from herpes simplex virus type 2 (HSV-2) infection. Test formulations were placed in the vaginas of progestin-treated mice prior to inoculation with HSV-2. Infection was determined by the presence of inflammation in the genital region and death. At a dose of virus that infected half of the control animals, 1% solutions of either lambda, kappa, or iota carrageenan prevented infection of almost all of the animals. Concentrations as low as 0.05% protected a large majority of the mice. At a dose of virus that infected all of the control mice, 1% solutions of carrageenans protected 85% of the inoculated mice. Other sulfated polysaccharides were less effective or showed no efficacy in preventing HSV-2 infection. These findings suggest that a vaginal formulation of carrageenan may be effective in blocking sexual transmission of HSV-2 in women.     

Protection against herpes simplex virus infection in mice by Corynebacterium parvum.

Corynebacterium parvum administered in mice prior to herpes simplex virus (HSV) infection significantly protected them against lethal encephalitis. This was seen both with a mouse strain highly susceptible to HSV and with one relatively resistant to HSV. Mice immunosuppressed by cyclophosphamide and showing an increased mortality after HSV infection were also protected by C. parvum pretreatment. However, C. parvum given simultaneously with or after HSV infection did not exert a therapeutic effect.     

Comparative study of macrophage response in mice after DNA immunization and infection with herpes simplex virus type 1

Functional activity of macrophages and intensity of T cell immune response in mice were studied after intravaginal and intraperitoneal infection with herpes simplex virus type 1 and DNA vaccination in combination with adjuvant treatment (recombinant granulocytemacrophage colony-stimulating factor and glucosaminylmuramyl dipeptide). DNA vaccination induced a virus-specific T cell immune response with no macrophagic inflammatory reaction. Infection with herpes simplex virus type 1 was accompanied by sustained inflammation, but not by the T cell immune response. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 140, No. 12, pp. 670–673, December, 2005     

Detection of antibody to viral proteins following primary infection with herpes simplex virus

Sera from patients with primary genital infection with herpes simplex virus (HSV) were tested by immunoblotting (IB) and radioimmunoprecipitation (RIP) analysis to determine the protein targets of antibody elicited by infection. The two tests detected antibody to different antigens: IB primarily detected reactivity with p40, a phosphorylated capsid protein, and RIP detected antibody to glycoprotein B, a viral envelope component. Furthermore, RIP detected antibody at an earlier stage of infection then IB. A nondenaturing version of IB was developed and used to investigate the role that the solubilisation of antigen plays in the sensitivity of each test for antibodies with different specificities.     

Murine epidermal antigen-presenting cells in primary and secondary T-cell proliferative responses to herpes simplex virus in vitro.

The role of epidermal Langerhans' cells in infection with herpes simplex virus (HSV) was investigated using a culture system that supports antigen-specific primary and secondary T-cell proliferative responses. Epidermal cell suspensions were capable of restimulating the response of in vivo primed T cells to UV-inactivated HSV. This capability was also present in cell suspensions enriched for Langerhans' cells, but was abrogated by the depletion of I-A-bearing cells. The magnitude, kinetics and phenotype of the responding cells were similar to those elicited when HSV was presented to primed T cells by antigen-presenting cells from the spleen. In marked contrast, whereas splenic antigen-presenting cells induced strong antigen-specific proliferation of unprimed T cells (primarily of the helper phenotype), Langerhans' cells failed to invoke any detectable reaction of such cells.     

Efficacy of herpes simplex virus type 1 immunization in protecting against acute and latent infection by herpes simplex virus type 2 in mice.

ICR mice were immunized with herpes simplex virus type 1 (HSV-1) and later challenged with HSV-2 by footpad inoculation. Both immunized animals and age-matched, nonimmunized controls were observed for ascending neurological disease and latent infection of spinal ganglia resulting from the HSV-2 challenge. Control animals had a 78% incidence of acute and latent infection compared with a 1.7% incidence in immunized mice. The data show immunity to HSV-1 is protective against both acute and latent infection by HSV-2.     

Latent herpes simplex virus in ganglia of mice after primary infection and reinoculation at a distant site

Summary Herpes simplex virus (HSV)-infected hairless mice with evidence of latent infection in spinal ganglia did not develop latent HSV infections in trigeminal ganglia upon reinfection in the oro-facial area. HSV-infected and PAA-treated mice without evidence of latent HSV infection in spinal ganglia were resistant to reinfection in the lumbar region, but not to that performed in the oro-facial area.This is publication No. 32 from the Cooperative Antiviral Testing Group of the Antiviral Substances Program, Development and Applications Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health.