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The herpes simplex virus type 1 strain 17 open reading frame RL1 encodes a polypeptide of apparent M(r) 37K equivalent to ICP34.5 of herpes simplex virus type 1 strain F.

The region between the 'a' sequence and the 5' end of the IE1 gene within the long repeat sequence of the herpes simplex virus (HSV) genome plays an important role in the neurovirulence of both HSV-1 strain F and HSV-1 strain 17. However, there has been controversy over the protein-coding potential of this region. Although an open reading frame (ORF) was predicted in HSV-1(F) and shown to encode a polypeptide called ICP34.5, only recently has a corresponding ORF, designated RL1, been recognized in HSV-1(17). To determine whether the HSV-1(17) ORF is expressed, we raised antipeptide sera against predicted amino acid sequences from RL1; one serum specifically recognized a 37K protein in HSV-1(17)-infected cell extracts. Compared with the corresponding HSV-1(F) polypeptide the HSV-1(17) protein has a lower apparent M(r), shows similar kinetics of accumulation and intracellular localization but may accumulate to lower levels than the HSV-1(F) protein. The non-neurovirulent HSV-1(17) deletion variant 1716 fails to synthesize detectable levels of ICP34.5. Thus we have established that HSV-1(17), like HSV-1(F), expresses ICP34.5, a protein important for HSV neurovirulence.

Amino Acid Sequence↗

Chronic granulomatous herpes simplex encephalitis in children.

Herpes simplex encephalitis is usually a monophasic acute illness but can cause chronic disease, particularly in children. Little information is available as to the histological substrate. We report the findings in 3 children. In 2 children, herpes encephalitis had occurred during the first 2 years, but both later developed intractable epilepsy that led to neurosurgery. The biopsies showed chronic granulomatous inflammation with foci of mineralization. One child made a good post-operative recovery. The other was found post-operatively to have herpes simplex virus type 1 (HSV-1) DNA and elevated titers of HSV IgM antibodies in the CSE He was given acyclovir but after initial improvement developed hemiparesis, with extensive signal change on MRI. Repeat biopsy revealed florid granulomatous inflammation with necrosis. The third patient was an infant who had had a cutaneous facial HSV-2 eruption soon after birth. This was treated with topical acyclovir, after which she remained well until 2 months, when she presented with a relatively non-specific illness, developed blisters of the right hand and foot, and died a few days later. Necropsy revealed severe granulomatous encephalitis, most extensive in the temporal lobe and insula, and associated with mineralization. Our findings indicate that herpes simplex encephalitis in children can be complicated by chronic granulomatous inflammation with mineralization. This pattern of disease may be an under-recognized complication of herpes simplex infection during the first few years of life.

Adolescent↗

Arrest of myelination and demyelination in rabbit retina induced by herpes simplex virus infection.

Herpes simplex virus was injected into the vitreous of suckling and adult rabbits. In the suckling rabbits the infection caused an arrested myelination of the strip. Further, the infected strips showed degenerative changes with splitting and distension of myelin sheaths which then disintegrated. Ultrastructurally, herpes simplex virus particles were found in both oligodendroglial cells and in astrocytes in the bundles. No increase in intraocular pressure was recorded during the inflammation. The infection spread along optic pathways to the opposite side. Inflammatory cells appeared at the surface and infiltrated the degenerating strip. Especially in the contralateral eye, an extensive inflammatory cell infiltration was seen among bundles of nerve fibres which showed partly well-preserved myelin and partly with signs of demyelination reminiscent of the picture of experimental allergic encephalomyelitis in the epiretinal strip.

Animals↗

Role of latency-associated transcript in herpes simplex virus infection.

Herpes simplex virus (HSV)-specified RNA transcript has been detected by in situ hybridization and by RNA blot analyses in latently infected peripheral nerve ganglia in experimentally infected mice and humans. Physical analysis of the nucleotide sequence, approximately 2,500, indicates possible splicing of the transcript into two overlapping open reading frames (ORF) and the presence of potential promoter elements. The latency-associated transcript, probably, is involved in the maintenance of latent herpes simplex virus infection; however, recent findings indicate that latent-phase transcription is involved in some in vivo reactivation.

Animals↗

Gene transfer to brain using herpes simplex virus vectors.

Herpes simplex virus type 1 represents an ideal candidate for development as a vehicle for gene transfer to postmitotic neurons of the central nervous system. The natural biology of this virus makes it well suited for this purpose as it is capable of infecting a variety of neuronal cell types in the brain where the viral genome can persist indefinitely in a latent state. In latency, the viral lytic genes are transcriptionally silent and a unique set of latency-associated transcripts are expressed. Two impediments to using herpes simplex virus vectors must be overcome: (1) A noncytotoxic mutant virus backbone must be engineered, and (2) a suitable promoter-regulator that stably expresses foreign genes from the vector genome during latency must be constructed. Deletion of specific immediate early genes from the vector can render the virus nontoxic to neurons in culture and in vivo following stereotactic inoculation into specific regions of the brain. Because these viruses cannot replicate, they enter latency on infection of central nervous system neurons. A number of viral and cellular promoters have been tested for their ability to express genes during latency. Strong viral promoters and neurospecific promoters display transient activity. Although the promoter regions for the latency-associated transcripts are highly active in the peripheral nervous system, they show low-level but persistent activity in the brain. Experiments are in progress to exploit RNA polymerase III gene promoters or novel recombinant promoters capable of auto-inducing their own expression in order to increase gene expression during latency in brain neurons.

Animals↗

A case of recurrent, isolated, simultaneous, bilateral herpes simplex lid infection.

BACKGROUND: Ocular herpes simplex is usually diagnosed by its typical clinical presentation. It is generally accepted to be a unilateral disease, with lid eruptions typically occurring in primary ocular herpes simplex, while absent or mild in recurrent disease. Recurrent ocular herpes simplex is generally thought to be characterized by corneal involvement. CASE REPORT: A 35-year-old woman had a 2-day history of a progressive bilateral, erythematous, vesicular rash of the upper and lower eyelids and associated preseptal cellulitis. She had a history of a recurrent, unilateral eyelid rash that was previously diagnosed as herpes zoster. The eyelid involvement was unusual because it was bilateral, severe, recurrent, vesicular, and isolated, with no additional ocular manifestations of herpes simplex. These atypical features are in contrast to the generally accepted manifestations of recurrent ocular herpes simplex. A cytologic evaluation and a viral culture confirmed infection by HSV Type 1. CONCLUSION: Lid involvement occurs in recurrent ocular herpes simplex disease more often than generally accepted, while simultaneous bilateral disease is uncommon. As in this case, when atypical presentations occur, critical review of the differential diagnosis and use of laboratory tests are helpful.

Acyclovir↗

Asymptomatic shedding of herpes simplex virus from the genital tract: uncertainty and its consequences for patient management. The Herpes Simplex Virus Advisory Panel.

A frequent component of the management of patients with genital herpes concerns the possibility of asymptomatic shedding and potential sexual transmission of the virus. Approaches intended to provide supportive counselling and reassurance of patients about these issues need now to be modified in the light of increasing data of the frequency of asymptomatic detection of virus and the effects of antiviral therapy on this phenomenon. Further studies to delineate the relationship between asymptomatic detection of HSV in the genital tract and the mechanism of sexual transmission of this virus need to be conducted before clinicians instigate antiviral suppressive treatment primarily to prevent sexual transmission of HSV. However, it is important that the new data and our greater understanding of the natural history of genital herpes is translated into accurate and comprehensible information for our patients.

Acyclovir↗

Delivery of a foreign gene to sympathetic preganglionic neurons using recombinant herpes simplex virus.

Two recombinant herpes simplex type 1 viruses expressing beta-galactosidase (encoded by the Escherichia coli lacZ gene) inserted into the unique long 41 (encoding virus host shutoff) or unique short 5 (encoding glycoprotein J) open reading frames were generated. Purified recombinants or wild-type herpes simplex type 1 were injected into the left adrenal gland of hamsters. Three days later, virus-infected neurons were detected in spinal cord sections from all infected hamsters. Neurons were visualized with beta-galactosidase histochemistry in spinal cord sections from hamsters infected with either of the recombinants but not with the wild-type virus. Wild-type virus could only be detected with immunocytochemistry. Insertional mutagenesis into the unique long 41 or unique short 5 regions of the herpes simplex genome by lacZ did not disrupt the neurotropic properties of the virus. Both recombinant viruses labelled the central nervous system sympathoadrenal preganglionic neurons as well as brainstem neurons. Because the virus host shutoff recombinant more readily crossed synapses to reach the brainstem compared to the glycoprotein J recombinant, the presence of glycoprotein J may facilitate cell to cell transmission in vivo. Both recombinants may be useful for the study of synaptic organization of neural circuits. Our recombinant viruses were less lytic yet neurovirulent after mutation of either glycoprotein J or virus host shutoff of herpes simplex virus type 1 wild-type. These recombinant viruses express the bacterial beta-galactosidase which is readily detectable using simple histochemistry. Inoculation of the adrenal gland or kidney with these viruses led to clear labelling of spinal cord cells. These viruses may be useful markers of specific neural circuits.

Animals↗

The immune response to herpes simplex virus: comparison of the specificity and relative titers of serum antibodies directed against viral polypeptides following primary herpes simplex virus type 1 infections.

Employing an immunoblotting technique, the polypeptide specificity and relative titers of anti-HSV IgG reactive with denaturation-resistant epitopes on HSV proteins were determined in patients experiencing primary HSV-1 infections at various anatomical sites. Early sera from previously seronegative patients with primary HSV-1 infections were found to have comparatively low levels of antibody directed against the major viral glycoprotein antigens (gB, gC, and gD) relative to titers present in sera of individuals with long-standing, latent orofacial HSV-1 infections. Patients with primary infections did however have high titers of antibody directed against a series of low molecular weight HSV polypeptide antigens. These antigens were found to be antigenically related to a structural component of virion nucleocapsids. At later times postinfection, titers of antibodies directed against other viral polypeptides including the major glycoproteins increased to levels more closely approximating those observed in latently infected individuals. These results indicate that the anti-HSV IgG detected by immunoblot analysis which appears earliest following primary infection is not directed against the known major infected cell or virion glycoprotein surface antigens but rather against an internal capsid protein of HSV.

Antibodies, Monoclonal↗