Latent Herpes Simplex Virus Infection Research Articles

Latent Herpes Simplex Virus Infections in Sensory Ganglia of Hairless Mice Prevented by Acycloguanosine

Acycloguanosine (ACG) was able to prevent the fatal outcome of herpes simplex virus-induced skin infections of the lumbosacral or orofacila area in hairless mice. Topical ACG treatment was more effective than systemic treatment in preventing the evolution of skin lesions. Acute ganglionic infections in the trigeminal ganglia were prevented by ACG, and latent ganglionic infections did not become established when the ACG treatment was initiated 3 h after infection. Serum antibody titers were, on the average, eight times higher in mice which developed latent ganglionic infections after ACG treatment than in mice without evidence of herpes simplex virus latency in ganglia. Reinoculation of ACG-treated mice at a site different from that of the primary inoculation did not lead to the establishment of a second latent infection with the homologous virus type when a latent infection was already present. In mice without evidence of latent infection after the primary inoculation, a latent infection at the site of reinoculation became established in 25% of the animals.

Interaction of Human Cells with Prostaglandins and Cyclic AMP Modulators

Abstract The release of prostaglandins (PG) has been incriminated in exacerbations of latent herpes simplex virus (HSV) infections in humans, but the mechanism(s) by which PG could precipitate a recurrence has not been adequately explored. In this study we determined the effect of PG-A1, B1, E1, E2, F2α, and other cAMP elevating agents had on complement (C)mediated lysis and antibody-dependent cell-mediated cytolysis (ADCC) of HSV-infected human fibroblasts (HuF). C-lysis was not inhibited by PG, phosphodiesterase inhibitors, or dibutyryl-cAMP regardless of the concentrations of reagent, human antiHSV, or C that was incubated with the HuF. As determined by 51Cr release, human mononuclear leukocytes (MNL) were inhibited from mediating ADCC by PGE1 or E2 (≥0.1 µg/ml), PGF2α or A1 (≥1.0 µg/ml), PGB1 (10 µg/ml), isoproterenol (≥10-6 M), theophylline (≥10-3 M), methyl-isobutyl-xanthine (≥10-4 M), and db-cAMP (≥10-4 M). The inhibitory effect these reagents had on ADCC was removed by washing the cells and no adverse effect on viability was noted. Another quantitative ADCC assay, antibody-dependent suppression of plaque formation, also indicated that PGE2 inhibited MNL-mediated ADCC, and showed the reagent had no effect on virus growth in HuF. Except for the 1.0 µg/ml concentrations of PGF2α and A1, the inhibition of ADCC produced by PG was correlated with significant elevations of cAMP in the human MNL. Finally, experiments showed that as the concentration of PGE2 added to the cultures increased, there was a decrease in both the number of MNL attached to the HuF and the amount of ADCC obtained. Thus, the data indicated that PGE2 inhibited cytolysis by interfering with attachment of the effector MNL to the antibody-coated target cells. In summary the studies support the proposition PG could cause exacerbation of HSV disease in patients by suppression of ADCC.

Route of infection, systemic host resistance, and integrity of ganglionic axons influence acute and latent herpes simplex virus infection of the superior cervical ganglion

The character of acute and latent herpes simplex virus (HSV) infection of the superior cervical ganglion (SCG) in mice depended on the route by which the virus reached the ganglion, the level of systemic host resistance, and the integrity of postganglionic nerves. Prevention of ganglionic infection by postganglionic neurectomy carried out before intraocular (i.o.) virus challenge established the importance of the neural route in the development of SCG infection. However, hematogenous virus dissemination also led to SCG infection although with reduced frequency compared to that with i.o. inoculation. Enhanced host systemic antiviral resistance had two divergent effects on ganglionic infection depending on the dose and timing of virus inoculation. Thus, both acute and latent ganglionic infections were concomitantly reduced when resistant C57B1/6 mice were challenged with low doses of virus or when less resistant BALB/c mice were actively immunized 1 week before virus challenge. On the other hand, when resistant mice were challenged with high doses of virus or when either active or passive (antibody) immunization was delayed long enough to assure viral access to the ganglion, intraganglionic viral replication during the acute phase of infection was reduced, but the prevalence of subsequent latent infection was either unaffected or actually enhanced. Postganglionic neurectomy, performed after virus had reached the ganglion, altered the course of SCG infection in a direction opposite that of immunization, augmenting the acute phase of viral replication while reducing latency. In athymic nude mice and mice immunosuppressed with cyclophosphamide, intraganglionic viral replication was prolonged. These results emphasize that host factors both extrinsic and intrinsic to the SCG modify the course of ganglionic infection.

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

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.

Orofacial Herpes Simplex Virus Infection in Hairless Mice: Latent Virus in Trigeminal Ganglia After Topical Antiviral Treatment

Inoculation of herpes simplex virus on the forehead and/or snout of hairless mice resulted in a significantly lower mortality rate than inoculation of the skin in the lumbosacral area. Latent herpes simplex virus infections were detected in all forehead-inoculated and in 90% of snout-inoculated mice. Phosphonoacetic acid was highly effective in preventing the development of skin lesions, and no latent infections were detected when phosphonoacetic acid ointment was applied 3 h after infection. Neither adenine arabinoside nor adenine arabinoside monophosphate prevented the establishment of latent infections in the trigeminal ganglia, although they protected the mice from the fatal outcome of the infection. The antibody response after adenine arabinoside or adenine arabinoside monophosphate treatment was similar to that observed in untreated animals, and it was six to eight times higher than in mice treated with phosphonoacetic acid. Mice without evidence of latent infection had, in general, lower serum antibody titers than those with latent infections in the ganglia. An analysis of the pathogenesis of herpes simplex virus infection in mice treated with adenine arabinoside showed that virus penetration into the nerve endings was delayed and that the amount of free virus in ganglionic homogenates was 10 to 100 times less than that for untreated mice.

Reactivation of latent herpes simplex virus infection of the autonomic nervous system by postganglionic neurectomy

Latent herpes simplex virus infection of the superior cervical autonomic ganglion was reactivated in vivo by postganglionic neurectomy. Two methods were used to demonstrate viral reactivation: (i) recovery of infectious herpes simplex virus in ganglion homogenates and (ii) acceleration of virus expression in ganglion explants in culture. Both the percentage of mice exhibiting reactivated ganglion infection and the viral titers detected in ganglia increased when neurectomized mice were treated with cyclophosphamide. Antithymocyte serum treatment prolonged the time course over which neurectomy-induced virus could be detected, but neither antithymocyte serum nor cyclophosphamide reactivated herpes simplex virus in the absence of neurectomy. These results demonstrate that postganlionic neurectomy provides a specific stimulus for herpes simplex virus reactivation and that cell-mediated immune defense are involved in the highly efficient elimination of reactivated virus from the ganglion in vivo.

Latent Herpes Simplex Virus Infection of Mice

C-57 albino weanling mice were latently infected with herpes simplex virus (Mp strain, type 1) by inoculation of 10(4) plaque forming units in the right hind footpad. The virus was demonstrable in explant cultures of the sacral dorsal root ganglia of these mice for as long as 18 months following inoculation. In addition, the virus was detectable when homogenates of these latently infected ganglia were placed on to differentiated organotypic cultures of fetal mouse dorsal root ganglia for as long as 8 months following inoculation of the mice. Virus was not demonstrable in these homogenates when they were placed on the Hela cells. The results suggest that during herpes simplex virus latent infection in mice there is continuous synthesis of infectious virus, probably in a highly localized area, which is detectable if a sensitive indicator substrate, such as these organotypic cultures, is used.

Latent Herpes Simplex Virus Infections in Sensory Ganglia of Mice After Topical Treatment with Adenine Arabinoside and Adenine Arabinoside Monophosphate

Adenine arabinoside (Ara-A) and Ara-A monosphosphate (Ara-AMP) ointments were able to prevent the fatal outcome of herpes simplex virus (HSV)-induced skin infection of the lumbosacral area in hairless mice. Ara-A and Ara-AMP had no irritating effect on the skin, but in a number of animals a protracted healing time of the skin lesions after the treatment was observed. The compounds conferred only a partial protection against the establishment of latent HSV infection in the spinal root ganglia of the treated animals. The immune response, as judged from levels of HSV-specific neutralizing serum antibody titers, was not impaired by the antiviral treatment.

Extraneural localisation of herpes simplex virus in latently infected guinea pigs

CHRONIC latent herpes simplex virus (HSV) infections are associated with tissues of the nervous system in experimentally infected mice and rabbits1,2 as well as in humans3–5. Cook and Stevens demonstrated, that, after inoclation into the skin, HSV migrates via the subserving nerves to the corresponding sensory ganglia6. The virus establishes there a latent infection which can be detected by methods of in vitro cultivation of the ganglia1–5. A consideration of the data obtained so far on the behaviour of latent HSV in mice, rabbits and men led Cook and Stevens as well as Baringer to the postulate, that latent HSV infections were restricted to tissues of the nervous system7,8. The failures to detect HSV in the skin during latent infections are consistent with this hypothesis9,10. Recurrent HSV infections are thought to arise by activation of the latent infection within the ganglia and the subsequent migration of the reactivated virus into the skin via the corresponding nerve fibres8,11. I have described recently experimental infections of guinea pigs with HSV type 2, which led to chronic latent infections of the animals with frequent spontaneously recurring lesions at the sites of initial inoculation12,13. In this report I present evidence that during the latent phase of the infection HSV can be recovered not only from nervous tissues but also from the skin at the site of the primary infection.

Immune response and latent infection after topical treatment of herpes simplex virus infection in hairless mice

Treatment of herpes simplex virus (HSV)-infected hairless mice with a 2% phosphonoacetic acid (PAA) ointment prevented the appearance of virus-induced skin lesions and subsequent central nervous system (CNS) involvement. Treatment started 24 h after infection significantly reduced the intensity of the skin lesions and also prevented CNS involvement. After four to six applications of PAA ointment, a moderate skin erythemia developed, followed by scaling and complete healing 7 days after cessation of the treatment. Mice treated early after HSV infection had low or undetectable levels of virus-specific antibodies but were completely resistant to reinfection. Early treatment prevented the development of a latent ganglionic infection, but treatment initiated 24 h after infection could not prevent the establishment of the latent infection. PAA-treated and HSV-infected mice with nondetectable levels of antibodies did not develop, with a single exception, a latent ganglionic infection unpon reinfection. The cell-mediated immune response determined by levels of [14C]thymidine incorporation in Ficoll-Hypaque-purified spleen lymphocytes cultures was low in PAA-treated mice; it increased slightly after challenge infection but was strong in mice that proved to harbor a latent HSV infection in the ganglia.

Pathogenesis of latent herpes simplex virus infection of the trigeminal ganglion in guinea pigs: effects of age, passive immunization, and hydrocortisone

Latent herpes simplex virus (HSV) infection of the trigeminal ganglion, after corneal inoculation of virus, was investigated in guinea pigs. The effects of several factors on the establishment of ganglionic latency were investigated. Latently infected guinea pigs were clinically normal, and virus was isolated from the trigeminal ganglia by co-cultivation. It was found that newborn guinea pigs were significantly more susceptible than adult animals to the development of latent HSV infection of the trigeminal ganglion. The susceptibility of newborn guinea pigs was very much decreased, however, if they received passive immunization with immune serum or if they were born of actively immunized mothers. On the other hand, the susceptibility of adult animals, usually somewhat resistant to the development of latent HSV ganglionic infection, was markedly increased by the parenteral administration of hydrocortisone.

Effects of 5-bromodeoxyuridine and 5-iododeoxyuridine on a latent herpes simplex virus infection.

A latent herpes simplex virus infection was established in rabbit kidney cells. Treatment of the cells with 5-bromo-2-deoxyuridine after the latent infection was established had no effect on the rate of virus recovery but did extend the latent period before active virus growth resumed. In contrast to this, treatment of cells with 5-bromo-2-deoxyuridine or 5-iodo-2-deoxyuridine prior to infection with virus increased the subsequent rate of virus recovery.

Herpes simplex virus infection in guinea pigs: an animal model for studying latent and recurrent herpes simplex virus infection

Footpad infection of guinea pigs with herpes simplex virus led to an acute local inflammatory reaction, followed by a persistent latent infection of lumbosacral dorsal root ganglia. Spontaneous reactivation of the latent virus occurred, leading to recurrent lesions at the site of the initial infection. Clinical observations and virological studies during the acute latent and recurrent infection are reported.

Chronic herpes simplex virus infection. Initiation in hamsters upon implantation of infected nonpermissive glial cells.

Neuroblastoma and transformed glial cell cultures vary from nonpermissive to completely permissive for infectious herpes simplex virus (HSV) production. Electron microscopy shows that (1) the amount of infectious virus produced by a cell is related to the extent to which the cell nuclear membrane becomes altered by the infection, and (2) in one transformed glial line which makes no infectious virus (the C-6 line) the nuclear membrane is not structurally altered at all and only incomplete virus particles are made. Implantation of C-6 cells into hamsters results in the formation of an astrocytoma; implantation of HSV-infected C-6 cells initiates a chronic HSV infection in the animal. These studies are significant because they suggest a mode of latent HSV infection, especially as it relates to the nervous system.