Maternal Herpes simplex virus type 2 encephalitis following Cesarean section

Herpes simplex virus type 2 (HSV-2) encephalitis is rare especially during pregnancy. In immunocompetent patients, HSV-2 meningitis (contrary to HSV-1 meningitis) is usually mild, without encephalitis. We report a rare case of maternal HSV-2 encephalitis following Cesarean section. The woman had no symptomatic genital lesion, and the infant was not infected. The route of meningeal infection (neuronal or hematogenous) is discussed.     

Induction of encephalitis in SJL mice by intranasal infection with herpes simplex virus type 1: a possible model of herpes simplex encephalitis in humans.

Herpes simplex encephalitis (HSE) is characterized by focal lesions of hemorrhage and necrosis, primarily in the inferior temporal lobe. Since immunosuppressed patients with HSE lack the focal inflammatory changes and temporal lobe localization, it has been suggested that the immune system participates in the pathogenesis of HSE. Evaluation of this hypothesis has been impeded by the lack of an immunologically defined animal model that resembles the human disease. Toward this end, 10 strains of inbred mice were infected intranasally with a neurovirulent clinical isolate of herpes simplex virus type 1. Most mice died without localizing signs of disease in the central nervous system. However, a significant number of SJL mice had a pattern of encephalitis highly reminiscent of that described in humans. To our knowledge, this is the first murine model that faithfully mimics this human disease, and thus it affords the opportunity to study the immunopathogenesis of HSE.     

Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS

Infections caused by herpes simplex virus (HSV) are a significant source of morbidity in immunocompromised patients. Acyclovir is often used prophylactically and therapeutically in patients with human immunodeficiency virus infection. The emergence of acyclovir-resistant strains of HSV capable of causing disease has been recognized. We report a case in which a thymidine kinase-deficient mutant of HSV caused extensive disease in a patient with AIDS. This case emphasizes that virus recovered from nonhealing lesions should be submitted for further study, which may advance our understanding of the interaction between host defense and drug-resistant strains.     

Expression of herpes simplex virus 1 glycoprotein B by a recombinant vaccinia virus and protection of mice against lethal herpes simplex virus 1 infection.

The herpes simplex virus 1 (HSV-1) strain F gene encoding glycoprotein gB was isolated and modified at the 5' end by in vitro oligonucleotide-directed mutagenesis. The modified gB gene was inserted into the vaccinia virus genome and expressed under the control of a vaccinia virus promoter. The mature gB glycoprotein produced by the vaccinia virus recombinant was glycosylated, was expressed at the cell surface, and was indistinguishable from authentic HSV-1 gB in terms of electrophoretic mobility. Mice immunized intradermally with the recombinant vaccinia virus produced gB-specific neutralizing antibodies and were resistant to a lethal HSV-1 challenge.     

Detection of herpes simplex virus type 1-IgM immune complexes in the brain of a patient with prolonged herpes encephalitis

A 56-year-old man with herpes encephalitis died 5.5 months after disease onset. Herpes simplex virus was isolated from minced temporal lobe after one month of cocultivation with green monkey kidney cells. The virus was identified as type 1 by neutralization and the fingerprinting pattern on restriction enzyme digestion. By immunofluorescence, IgM deposition was seen in the cerebral vascular walls. After dissociation of IgM with 3.0 M NaSCN, viral antigen was noted at the same loci as the IgM deposition. Histopathology showed marked perivascular cuffings, approximately 80% of which consisted of T cells and widely distributed necrotic foci. When the patient's serum and spinal fluid were analyzed by the immunoblotting method, the spinal fluid contained antibodies that were reactive with two very-high-molecular-weight viral polypeptides.     

Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis

Cerebrospinal fluid (CSF) specimens were obtained from patients with presumed herpes simplex encephalitis who underwent brain biopsy for diagnostic confirmation. Coded CSF specimens were fixed on nitrocellulose filter paper and probed with a pool of monoclonal antibodies directed against four herpes simplex virus glycoproteins (gB, gC, gD, and gE). Herpes simplex virus antigen was detected in 35 of 40 specimens obtained from 26 biopsy-positive patients. In contrast, only three of 25 specimens from 17 biopsy-negative patients gave positive results by this assay. An additional 30 CSF specimens from patients with proven bacterial and fungal infections were all negative by this assay. For all specimens tested, the sensitivity and specificity of the assay were both 88%. However, when results were evaluated by patient, the sensitivity was 92% (24 of 26) with a specificity of 82% (14 of 17). Among specimens collected one week or later after disease onset, the sensitivity was 100%, with a specificity of 93%.     

Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis

Human neonates infected with herpes simplex virus 1 (HSV-1) develop one of three distinct patterns of infection: (i) infection limited to the skin, eye or mouth; (ii) infection of the CNS; or (iii) disseminated infection. The disseminated form usually involves the liver, adrenal gland, and lung, and resembles the clinical picture of bacterial sepsis. This spectrum of symptoms in HSV-1-infected neonates suggests that inflammatory cytokines play a significant role in the pathogenesis of the disease. Recent studies suggest that the Toll-like receptors (TLRs) may play an important role in the induction of inflammatory cytokines in response to viruses. TLRs are mammalian homologues of Toll, a Drosophila protein that is essential for host defense against infection. Engagement of TLRs by bacterial, viral, or fungal components leads to the production and release of cytokines and other antimicrobial products. Here, we demonstrate that TLR2 mediates the inflammatory cytokine response to HSV-1 by using both transfected cell lines and knockout mice. Studies of infected mice revealed that HSV-1 induced a blunted cytokine response in TLR2(-/-) mice. Brain levels of monocyte chemoattractant protein 1 chemokine were significantly lower in TLR2(-/-) mice than in either wild-type or TLR4(-/-) mice. TLR2(-/-) mice had reduced mortality compared with wild-type mice. The differences between TLR2(-/-) mice and both wild-type and TLR4(-/-) mice in the induction of monocyte chemoattractant protein 1, brain inflammation, or mortality could not be accounted for on the basis of virus levels. Thus, these studies suggest the TLR2-mediated cytokine response to HSV-1 is detrimental to the host.     

Chemotherapy of herpes simplex virus encephalitis in mice by direct intracerebral injection.

The effects of 9-beta-D-arabinofuranosyladenine-5'-phosphate (ara-A-5'-P) on herpes simplex virus encephalitis in mice were studied. This drug is a monophosphate derivative of adenine arabinoside (ara-A). When administered by the intracerebral (ic) route, ara-A-5'-P was highly effective in virus-infected mice in the 17-20 g weight range provided therapy was begun before clinical symptoms of encephalitis appeared. The most effective dose schedule was found to be three daily ic injections totaling 400 micrograms/day (20 mg/kg) beginning on the third day after injection. Such treatment resulted in a survival rate of 50%-75% among infected mice after six months. In the early stages of many experiments, 90%-100% of the controls died whereas all of the treated animals survived.     

Seropositivity to herpes simplex virus type 2, but not type 1 is associated with premature cardiovascular diseases: A population-based cross-sectional study

Objective

Thirty-five years after herpesviruses were suggested to induce atherosclerosis sero-epidemiological evidence on Herpes Simplex Viruses (HSV) remains sparse and controversial. We aimed to investigate the relationship between HSV-1 and HSV-2 infections and cardiovascular diseases (CVD).

Methods and results

A population-based cross-sectional study was conducted among 14,415 participants (mean age 34.3 years, range 20–49) of the National Health and Nutrition Examination Survey 1999–2010. Serum IgG-antibodies to HSV were measured by enzymatic immunodot assay and CVD were self-reported. CVD prevalence was 1.8%; 51.3% of participants were infected with HSV-1, 7.5% with HSV-2, and 15.2% with both. After adjusting for demographics, socioeconomic status, comorbidities, STD, and CVD risk factors, seropositivity to HSV-2 was positively associated with CVD (Odds ratio [OR] 1.56, 95% confidence interval [CI]: 1.09–2.21, P = 0.014), but not with HSV-1 (OR 1.13, 95% CI: 0.79–1.62).

Conclusion

HSV-2 may be associated with premature CVD, but not HSV-1.     

Interleukin-2 protects neonatal mice from lethal herpes simplex virus infection: a macrophage-mediated, gamma interferon-induced mechanism

Administration of human recombinant interleukin-2 (IL-2) protected neonatal mice from a lethal herpes simplex virus (HSV) infection. Protection was not associated with viral antibody production, enhanced natural killer cell cytotoxicity, or intrinsic resistance of macrophages to viral infection. Protection was associated with increased macrophage-mediated antiviral antibody-dependent cellular cytotoxicity (ADCC). Spleen cells from IL-2-treated neonatal mice and from neonatal mice that were treated in vitro with IL-2 transferred protection to neonatal mice. These cells, by adherence, silica, and asialo GM 1 antibody treatment, were shown to be macrophages. IL-2 treatment in vitro enhanced the neonatal macrophages' ADCC function and superoxide release. Similar protection was induced by gamma interferon (IFN-gamma)-treated spleen cells. Antibody to IFN-gamma ablated both IFN-gamma- and IL-2-induced protection by adherent spleen cells. Thus, IL-2-mediated protection against murine neonatal HSV infection was affected by stimulated macrophage activity, via helper T cell-produced IFN-gamma.     

Uninfected cell polymerase efficiently transcribes early but not late herpes simplex virus type 1 mRNA.

The sequences of the DNAs encoding the 5' ends of one early and one late herpes simplex virus type 1 mRNA were analyzed, and the 5' ends of these mRNA species were precisely located. Neither mRNA species is spliced and the noncoding strand of the DNA contains recognizable T-A-T-A and C-A-T boxes upstream from their respective 5' ends. The early mRNA was efficiently transcribed by a commercially available uninfected cell lysate system, but the late mRNA was not. This difference between early and late mRNAs appears to be general in this virus.     

Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis

Cerebrospinal fluid (CSF) and serum specimens from patients with presumed herpes simplex encephalitis (HSE) were characterized for antibodies to herpes simplex virus (HSV) by immunoblot and other immunoassays. Specimens from patients proven to have HSE (biopsy-proven) were compared with those from patients with other diseases diagnosed by brain biopsy (biopsy-negative for HSV). Immunoblot of CSF demonstrated that antibodies to HSV-specific polypeptides, particularly to glycoprotein B, were present in a matched serum specimen. When purified glycoprotein B was used to detect CSF antibodies, 34 of 35 specimens from biopsy-proven patients were reactive (97% sensitivity) compared with only six of 22 specimens obtained from biopsy-negative patients (73% specificity). If leakage of antibodies to a marker virus (adenovirus) was determined and controlled, the specificity increased to 100%. These diagnostic assays provide useful tools for the retrospective assessment of CSF specimens obtained from patients with presumed HSE.     

Effect of pretreatment with toll-like receptor agonists in a mouse model of herpes simplex virus type 1 encephalitis

BACKGROUND: We evaluated the effect of pretreatment with Toll-like receptor (TLR) agonists in a mouse model of herpes simplex virus type 1 (HSV-1) encephalitis. METHODS: BALB/c mice received a single intraperitoneal or intranasal injection of polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist; lipopolysaccharide (LPS), a TLR4 agonist; oligodeoxynucleotide (ODN), a TLR9 agonist; or control vehicle. Twenty-four hours later, animals were infected with 5000 plaque-forming units of HSV-1. RESULTS: Mice that received intraperitoneal pretreatment with vehicle, LPS, and poly I:C had survival rates of 7%, 13%, and 56%, respectively, and mean life expectancies of 156.80+/-9.56, 176.00+/-9.24, and 213.00+/-7.71 h, respectively (p< .05, poly I:C group vs. other groups). Similarly, intranasal pretreatment with vehicle, LPS, ODN, and poly I:C were associated with survival rates of 20%, 47%, 60%, and 94%, respectively, and mean life expectancies of 153.60+/-11.71, 188.80+/-12.97, 204.80+/-11.73, and 234.00+/-5.81 h, respectively (p< .05, ODN and poly I:C groups vs. vehicle group). Pretreatment with intranasal poly I:C induced early expression of several immune genes in the brain and resulted in a significantly lower virus load. CONCLUSION: TLR3 stimulation by poly I:C 24 h before infection reinforces a natural innate immune mechanism of neuroprotection against HSV-1.     

T lymphocytes in genital lymph nodes protect mice from intravaginal infection with herpes simplex virus type 2

Herpes simplex virus type 2 (HSV-2) is a human venereal pathogen that causes lethal neurological illness after intravaginal inoculation into BALB/cJ mice. Intravaginal vaccination of mice with an attenuated strain of HSV-2 rapidly induces immunity to a lethal intravaginal challenge with wild-type HSV-2. This resistance is transferrable to syngeneic mice with genital lymph node (GLN) cells but not with cells from other lymphoid sources. Here we demonstrate that minimal numbers of HSV-2-stimulated GLN T lymphocytes are required for resistance to genital infection by HSV-2 and that such cells migrate preferentially into HSV-2-infected genital tissue. Furthermore, the results suggest that HSV-2-specific cytotoxic T lymphocytes from the GLN may be one effector cell population participating locally in genital immunity to the virus. These findings indicate that mucosal immunity to genital HSV-2 infection requires the antigen stimulation of migratory T cells in the GLN.