Simian TRIM5α proteins reduce replication of herpes simplex virus

Old World monkey TRIM5α proteins are known to block the replication of human immunodeficiency virus and other retroviruses in a species-specific fashion. In this report, we show that specific forms of simian TRIM5α proteins can restrict herpes simplex virus (HSV) infection. To define the effect of TRIM5α on HSV replication, we examined HSV infection in HeLa cell lines that stably express simian and human orthologs of TRIM5α proteins. We demonstrated that several simian TRIM5α proteins can restrict HSV replication, with the TRIM5α protein of rhesus macaques showing the strongest inhibition of HSV infection. We also found that the level of the inhibition of virus replication was viral strain-specific. TRIM5α is likely to inhibit HSV at the early stage of infection; however, at later times of infection, the levels of TRIM5α are significantly decreased. Thus, some TRIM5α proteins exhibit antiviral effects that extend beyond retroviral infections, but HSV may be able to reduce this restriction by reducing TRIM5α levels during the later phases of virus replication. Our results also argue that TRIM5α is only part of the reduced level of HSV replication in rhesus macaques, which are known to be less susceptible to HSV infection than other primates.     

Acyclovir-resistant herpes simplex encephalitis in a patient treated with anti-tumor necrosis factor-α monoclonal antibodies

Herpes simplex virus is the most common cause of severe sporadic encephalitis. We report a case of herpes simplex type 1-encephalitis in a 50-year-old woman receiving anti-tumor necrosis factor-α monoclonal antibodies adalimumab. Although she was an acyclovir naïve patient, a mixed viral population (wild-type and acyclovir-resistant bearing a thymidine-kinase mutation) was identified in the cerebrospinal fluid. The virus in cerebrospinal fluid evolved and a second thymidine-kinase mutant virus emerged. Combined foscavir and acyclovir treatment resolved the herpes simplex encephalitis. To our knowledge, this is the first report of acyclovir-resistant herpes simplex encephalitis in a patient treated with adalimumab.     

Enhancement by TNF-α of reactivation and replication of latent herpes simplex virus from trigeminal ganglia of mice

Summary The influence of tumor-necrosis-factor- (TNF-), granulocytemacrophage colony-stimulating factor (GM-CSF), interleukine-1 (IL-1) and IL-3 on the in vitro reactivation frequency and replication rate of trigeminal ganglia of mice latently infected with herpes simplex virus (HSV) strain KOS was studied. It could be demonstrated that TNF- and possibility GM-CSF, but not IL-1 and IL-3, enhanced the reactivation frequency and replication of HSV. Interferon / (IFN/) prevented reactivation and replication.     

What's new in vaccines against herpes simplex infections?

Herpes simplex viruses (HSV) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy HSV infections remain a public health problem. Vaccines offer the possibility for controlling the spread and limiting HSV disease, two strategies for herpes vaccination: prophylactic immunization or therapeutic immunization. The article discusses the results of different studies, in particular, concerning recombinant vaccines, DISC vaccines and DNA vaccines.     

Anti-CD8 treatment alters interleukin-4 but not interferon-γ mRNA levels in murine sensory ganglia during herpes simplex virus infection

Summary.  Clearance of herpes simplex virus (HSV) from sensory ganglia of infected mice is dependent on CD8⁺ cells but not on the death of infected neurons. The mechanism of action of CD8⁺ cells in HSV infected ganglia is therefore unknown. The determine which cytokines might be involved in the CD8⁺ cell dependent response to ganglionic HSV infection, IL-2, IL-4, IL-6, IL-10, and IFN-γ mRNA levels were measured in infected ganglia from immunocompetent and anti-CD8 treated mice. Anti-CD8 treatment increased the abundance of mRNA encoding IL-4, and, to a lesser extent, IL-2, and IL-6. Significantly, IFN-γ mRNA was not affected. Received May 17, 1999 Accepted June 29, 1999     

Consequences of CXCL10 and IL-6 induction by the murine IFN-α1 transgene in ocular herpes simplex virus type 1 infection

Herpes simplex virus type 1 infection of the mouse eye results in an impressive inflammatory response culminating in the death of the animal or the establishment of a “latent” infection depending on a number of ill-defined variables that include components of the innate and adaptive immune system. The application of type I interferon transgenes has been found to antagonize viral replication and spread from the eye to the nervous system. Associated with the in situ transfection of the cornea is the upregulation of two inflammatory molecules, interleukin-6 and CXCL10. In this article, we will further examine the contribution these molecules may have in the host response to ocular infection with herpes simplex virus type 1.     

IFN-α cannot substitute lack of IFN-γ responsiveness in cells of an IFN-γR1 deficient patient

Patients with complete IFN-γR deficiency are unable to respond to IFN-γ and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-α and IFN-γ share signalling pathways, treatment with IFN-α has been proposed in complete IFN-γR deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-γR1 with IFN-α and IFN-γ, to establish whether IFN-α would substitute for IFN-γ effects. IFN-α induced STAT1 phosphorylation in monocytes of the IFN-γR1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-α inhibited the priming effect of IFN-γ on LPS-induced pro-inflammatory cytokine release. Finally, IFN-γ but not IFN-α induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-α in IFN-γR-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-α may even adversely affect host defence against Mycobacteria.     

Anti-tumoral capabilities of effector cells after IFN-α or CpG-motif treatment of cocultured dendritic cells

Introduction Ex vivo expansion of monocyte-derived dendritic cells (mDCs) and subsequent coculture with autologous cytokine-induced killer (CIK) cells is an established system to create specific and non-specific anti-tumoral immunity. mDCs constitute the most frequently applied DC subset in clinical studies. One recently published approach to optimize the immunological functions of the DC/CIK cell system is the replacement of interleukin (IL)-4 by interferon (IFN)-α in the maturation process of the DCs. Materials and Methods The expressions of relevant surface antigens of IL-4-DCs and IFNα-DCs by flow cytometry and the anti-tumoral activation of effector cells cocultured with both types of DCs using cytotoxicity assays were compared. In addition, short-term coculture experiments with both types of DCs and IFNγ-LAK effector cells were performed and compared with standard CIK cell coculture experiments. Results Regarding the expressions of functionally relevant surface markers, no differences could be detected for CD80, CD83, and HLA-DR between IFNα-DCs and IL-4-DCs, whereas the mean fluorescence intensities of CD40, CD86, CD54, and HLA-ABC were decreased and the expression of CD14 was increased for IFNγ-DCs. Moreover, no enhancement of cytotoxicity of cocultured CIK cells against tumor cell lines (A498 and SW480) was detected by the use of IFNα-DCs. Additionally, coculture experiments with IFNγ-LAK cells were performed and unexpectedly higher lysis rates in comparison with the established IL-4-DC/CIK coculture model was observed. Early incubation of the mDCs with several CpG-ODNs failed to increase the anti-tumoral cytotoxicity of the cocultured IFNγ-LAK cells. Conclusions These results demonstrate that in the mDC/CIK cell system, IFNα-DCs are not superior in inducing anti-tumoral cytotoxicity and even moderately inferior regarding the expression of functionally relevant surface markers compared with IL-4-DCs. Michael Erhardt and Ingo G. H. Schmidt-Wolf contributed equally.     

Are latent,immediate-early genes of herpes simplex virus-1 essential in causing trigeminal neuralgia?

The etiology and pathogenesis of major trigeminal neuralgia remain largely unknown, but are believed to result from an irritative lesion near the semilunar ganglion. We suggest that its primary cause is a single, active DNA sequence in the persistent but non-integrated genome of latent herpes simplex virus type 1 commonly observed in a few infected A-delta nerve fibers of the cheek. Facial pain occurs as a result of herpes virus reactivation and when supplies of neurotrophins controlling normal transport functions of axolemmal ion channels become depleted.     

Epidemiology of herpes simplex virus types 1 and 2 in Germany: what has changed?

Infections with herpes simplex virus (HSV) types 1 and 2 are widespread in all human populations and result in persistent and latent infections. HSV-1 is commonly responsible for orofacial, HSV-2 more likely causes genital lesions. Herpes genitalis is one of the most important sexually transmitted diseases; furthermore, there are severe diseases associated with HSV (e.g., encephalitis). Over the last years an increase in clinical manifestations of HSV has been reported, and HSV-1 has been increasingly discussed as causative agent of herpes genitalis. We retrospectively evaluated the laboratory results of our routine diagnostic service for HSV infections, looking for changes of HSV epidemiology in recent years. Specimens from 2,678 herpes patients were obtained between 1 January 1996 and 31 March 2002. Using cell culture, the presence of HSV was investigated in swabs taken from different body sites, and clinical data on HSV localization and type were evaluated. We found 345 patients positive for HSV-1 and 212 positive for HSV-2. Clinical data were available from 72.1% of the patients with HSV-1, and 61.3% of those with HSV-2 infection. In genital herpes HSV-1 was the causative agent in 20% of men and in 25% of women. In patients suffering from orofacial herpes HSV-2 was detected in 7% of men and in 4% of women. To evaluate the frequency of neurological HSV diseases, 2,406 cerebrospinal fluid samples (CSF) from 2,121 patients suspected of meningitis or encephalitis were tested for HSV DNA by the polymerase chain reaction. Among those patients, 120 showed CSF positive for HSV DNA. Serum surveys of HSV-1 and HSV-2 infection recently established in our region were compared to similar studies performed in Germany 25 years ago. We found that seroprevalences have not changed over the last 25 years and that neurological HSV diseases are rare. However, as in the USA, a significant percentage of herpes genitalis is caused by HSV-1 in Germany.     

Sequence analysis of herpes simplex virusgB gene homologs of two platyrrhine monkey α-herpesviruses

Summary Homologs of the herpes simplex virusgB gene were identified in two -herpesviruses of platyrrhine monkeys, Herpesvirus saimiri 1 (HVS 1) and H. ateles 1 (HVA 1). These genes were cloned and sequenced in their entirety. Analysis of the predicted amino acid sequences indicated that the gB glycoproteins of these two viruses are of similar size, have 10 Cys residues and 5 potential N-linked glycosylation sites which align exactly with those in other primate -herpesvirus gB polypeptides, and have a similar distribution of predicted secondary structural features, all of which indicate a conserved structure of the gB polypeptide. Alignment of these two gB sequences with those of four other primate -herpesviruses (SA 8, B virus, HSV 1 and HSV 2) revealed localized regions of extensive sequence divergence as well as highly conserved regions. On comparison of the six primate virus gB sequences, the gBs of the two platyrrhine monkey viruses form a subgroup separate from that of the four catarrhine virus gBs. The degree of relatedness of the HVA 1 and HVS 1 gB sequences to each other was equivalent to the degree of relatedness between the human and the cercopithecine monkey virus gB sequences.     

Safety of anti-TNFα agents in the treatment of psoriasis and psoriatic arthritis

Context: The efficacy and favorable safety profile of anti-tumor necrosis factor (TNF) agents in the treatment of psoriasis and psoriatic arthritis (PsA) are supported by several randomized controlled studies and meta-analyses. However, some concerns on the long-term safety of these drugs still exist, as these studies generally included small patient numbers and were performed in selected patient populations.

Objective: This review presents and discusses current evidence on the safety of anti-TNFα agents in patients with psoriasis and PsA, with a focus on European registry studies and case reports of particular importance.

Methods: Key studies on the safety of anti-TNFα agents in the treatment of adult patients with psoriasis or PsA were identified by a MEDLINE search (last updated 10 November 2011) based on several interrelated queries, with a focus on European registries. Other studies and case reports were included if deemed relevant. Studies concerning other conditions, such as rheumatoid arthritis (RA), were included as appropriate when data in psoriatic disease were unavailable or insufficient.

Results: Available data on the safety of anti-TNFα agents such as etanercept in psoriasis and PsA appear reassuring, even if some concerns still exist. Most notably, data suggest a higher incidence of infection and lymphoma amongst patients treated with the anti-TNFα monoclonal antibodies infliximab and adalimumab compared with etanercept.

Conclusion: The overall safety profile of monoclonal antibodies in patients with psoriasis, PsA and RA seems less favorable than that of etanercept, particularly in terms of risk of infection and hepatotoxicity.     

TNFα receptor knockout in mice reduces adverse effects of magnesium deficiency on bone

Epidemiologic studies have linked low dietary magnesium (Mg) intake to osteoporosis. Dietary Mg restriction in animal models has demonstrated a decrease in bone mass and an increase in skeletal fragility. The exact mechanism for the decrease in bone mass is not clear but a decrease in osteoblast number and an increase in osteoclast number (Oc.No/B.Pm) suggests an uncoupling of bone formation and bone resorption favoring skeletal loss. Mg depletion results in an increase in inflammatory cytokines, which could explain the increase in bone resorption. We have previously demonstrated an increase in TNFα in bone from Mg deficient rodents. Here we report results of a 3 week study of a low magnesium (LM) diet and normal Mg diet in 35-day-old TNFα receptor knockout mice (TNF-r-KO) versus wild type (WT) control mice. Our results indicated that a LM diet resulted in a greater increase in Oc.No/B.Pm in the WT mice, with a trend toward greater eroded bone perimeter, as compared to TNF-r-KO. These findings suggest that TNFα may play a role in Mg deficiency-induced bone loss.     

Relationship of herpes simplex encephalitis and transcranial direct current stimulation–a case report

We report a rare case of relapsing herpes simplex encephalitis in a-37-year-old patient which was previously confirmed by positive polymerase chain reaction, herpes simplex virus (HSV) type1 IgG antibodies in cerebrospinal fluid and characterized on MRI. During the first admission, he was treated with continuous acyclovir treatment for one month with clinical improvement except for residual aphasia, for which he received a course of outpatient transcranial direct current stimulation (tDCS). A constant current of 1.2 mA was applied for 20 min twice daily. After the 4th day the patient was found to be irritable and uncooperative by staff and family members. A subsequent MRI showed significant deterioration of the lesion on comparison to the first MRI which led to discontinuation of tDCS.The relatively rapid exacerbation of HSV in only a few days is unusual. Our aim is to discuss if tDCS is related to HSV relapse and in doing so highlight possible mechanisms.     

The role of CCR1 and therapeutic effects of anti-CCL3 antibody in herpes simplex virus-induced Behçet's disease mouse model

Behçet's disease (BD) is a chronic systemic inflammatory disease with unclear etiopathogenesis. Although gene variants of CC chemokine receptor type 1 (CCR1) have been reported, the protein expression of CCR1 in patients with BD remains unclear. The objective of this study was to analyze the frequencies of CCR1⁺ cells in a herpes simplex virus-induced mouse model of BD. The frequencies of CCR1⁺ cells on the surface and in the cytoplasm of peripheral blood mononuclear cells and lymph nodes were analyzed by flow cytometry. The CCR1⁺ cells were significantly down-regulated in BD mice compared with the normal control and symptom-free control mice. Colchicine and pentoxifylline treatment improved the symptoms of BD and increased the frequencies of CCR1⁺ cells in BD mice. Treatment with chemokine CC motif ligand 3 (CCL3), a ligand of CCR1, caused BD symptoms to deteriorate in 10 of 16 BD mice (62·5%) via down-regulation of CCR1⁺ cells. Anti-CCL3 antibody treatment ameliorated BD symptoms in 10 of 20 mice (50%) and significantly decreased the disease severity score compared with CCL3-treated BD mice (P = 0·01) via up-regulation of CCR1⁺ cell frequencies. In patients with BD, plasma levels of CCL3 in an active state were significantly higher than in healthy control individuals (P = 0·02). These results show that the up-regulation of CCR1⁺ cells was related to the control of systemic inflammation of BD in mouse models.     

IFN-γ induces IFN-α and IFN-β expressions in cultured rat intestinal mucosa microvascular endothelial cells

Although researchers have recently begun to pay more attention to the immunological characteristics of microvascular endothelial cells (MVECs), there are no reports on whether activation of MVECs by interferon-γ (IFN-γ) exerts any influence on the expressions of IFN-α/β. In the present study, we examined the influence of IFN-γ on the expressions of IFN-α/β in rat intestinal mucous MVECs (RIMMVECs). Different concentrations of IFN-γ were used to stimulate cultured RIMMVECs in vitro, and the cells and cell supernatants were collected at different time intervals. The influence of IFN-γ on the expressions of IFN-α/β in the RIMMVECs was examined at the mRNA and protein levels by real-time quantitative PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The results indicated that IFN-γ was able to activate RIMMVECs, thereby leading to upregulated expressions of IFN-α/β. The real-time quantitative PCR analyses indicated that the IFN-α/β mRNA expression levels in RIMMVECs achieved their peak values after stimulation with IFN-γ at 20?ng/mL for 6?h and were increased by 14.88- and 3.82-fold, respectively, when compared with the levels in negative control cells. The ELISA analyses revealed that the IFN-α/β protein expression levels achieved their peak values after stimulation with IFN-γ at 40?ng/mL. The expression of IFN-α protein achieved its peak value at 12?h, while the expression of IFN-β protein achieved its peak value after 6?h. The present results suggest that the expression and secretion of IFNs may participate in the immunologic barrier function of MVECs.