herpes
Agents and strategies in development for improved management of herpes simplex virus infection and disease.

Kleymann G.

Leopoldshoherstrasse 7, D-32107 Bad-Salzuflen, Germany.

The quiet pandemic of herpes simplex virus (HSV) infections has plagued humanity since ancient times, causing mucocutaneous infection such as herpes labialis and herpes genitalis. Disease symptoms often interfere with every-day activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immuno-compromised patient population. After infection the virus persists for life in neurons of the host in a latent form, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available. So far, vaccines, ILs, IFNs, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or non-specific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. The recently discovered inhibitors of the HSV helicase-primase are the most potent development candidates today. These antiviral agents act by a novel mechanism of action and display low resistance rates in vitro and superior efficacy in animal models. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15757392&dopt=Abstract herpes medicine



herpes
Homing in on the Cellular Immune Response to HSV-2 in Humans*.

Koelle DM, Gonzalez JC, Johnson AS.

Department of Medicine, University of Washington, Seattle, WA, USA.

Koelle DM, Gonzalez JC, Johnson AS. Homing in on the cellular immune response to HSV-2 in humans. AJRI 2005; 53:172-181 (c) Blackwell Munksgaard, 2005Problem: Genital herpes simplex infections are generally limited to epithelia and neurons. Vaccines have had activity in herpes simplex virus (HSV)-seronegative women only. Understanding how HSV-specific T cells traffic to infected sites may assist in vaccine design. Method of Study: Herpes simplex virus epitopes recognized by HSV-specific CD8 T cells were identified and used to make fluorescent human leukocyte antigen (HLA)-peptide tetramers. Molecules related to lymphocyte rolling adhesion were studied by flow cytometry and cell binding. HSV-specific CD4 T cells identified ex vivo by cytokine accumulation or activation marker expression, or detected in vitro by 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester (CFSE) dilution, were similarly investigated. Results: Herpes simplex virus-specific T cells are 10- to 100-fold more prevalent in lesional skin compared with blood and greatly enriched in lesions compared with normal skin. Diverse viral antigens are recognized by HSV-specific T cells. Functionally active E-selectin ligand, and cutaneous lymphocyte antigen (CLA), are expressed by circulating HSV-2-specific CD8 cells. CD4 cells display lower levels of CLA that are dramatically up-regulated upon re-stimulation with antigen. Conclusions: Herpes simplex virus-2-specific CD8 and CD4 T cells differ in constitutive expression of skin homing molecules. Vaccines designed to induce proper homing are postulated to have increased efficacy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15760378&dopt=Abstract herpes medicine



herpes
Plasmacytoid dendritic cell reconstitution following bone marrow transplantation: subnormal recovery and functional deficit of IFN-alpha/beta production in response to herpes simplex virus.

Giraud S, Dhedin N, Gary-Gouy H, Lebon P, Vernant JP, Dalloul A.

INSERM U131, Hopital Antoine Beclere, Clamart, France.

Infections with herpes viruses were frequent after bone marrow transplantation (BMT) before the preventive use of antiviral drugs, suggesting a deficit of innate immunity. A retrospective phenotypical and functional study was carried out on 25 patients 1-36 months after allogeneic BMT. Leukocyte counts followed a normal reconstitution, including natural killer (NK) cells and monocytes. Plasmacytoid dendritic cell (PDC) counts increased steadily, although they remained below normal values after 2 years. Most patients produced less interferon- alpha/beta (IFN-alphabeta) in vitro than healthy controls after infection with herpes simplex virus type 1 (HSV-1), whereas they responded normally to Sendai virus (SV). In addition, 6 patients had biologic signs of infection with herpes viruses, confirming a specific immunologic deficit against these viruses. IFN production was not correlated to PDC counts or to the occurrence of graft-versus-host disease (GVHD). Because all patients were under immunosuppressive treatment, we investigated the effect of drugs on IFN production by mononuclear cells. Glucocorticoids and cyclosporine A inhibited IFN production by infected leukocytes, with a predominant action on HSV-1-infected PDC. The inability of transplanted patients to mount an efficient immune response to herpes viruses may be partly related to drug toxicity toward cells of the innate immune system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15767787&dopt=Abstract herpes medicine



herpes
Cloning of the koi herpes virus (KHV) gene encoding thymidine kinase and its use for a highly sensitive PCR based diagnosis.

Bercovier H, Fishman Y, Nahary R, Sinai S, Zlotkin A, Eyngor M, Gilad O, Eldar A, Hedrick RP.

BACKGROUND: Outbreaks with mass mortality among common carp Cyprinus carpio carpio and koi Cyprinus carpio koi have occurred worldwide since 1998. The herpes-like virus isolated from diseased fish is different from Herpesvirus cyprini and channel catfish virus and was accordingly designated koi herpes virus (KHV). Diagnosis of KHV infection based on viral isolation and current PCR assays has a limited sensitivity and therefore new tools for the diagnosis of KHV infections are necessary. RESULTS: A robust and sensitive PCR assay based on a defined gene sequence of KHV was developed to improve the diagnosis of KHV infection. From a KHV genomic library, a hypothetical thymidine kinase gene (TK) was identified, subcloned and expressed as a recombinant protein. Preliminary characterization of the recombinant TK showed that it has a kinase activity using dTTP but not dCTP as a substrate. A PCR assay based on primers selected from the defined DNA sequence of the TK gene was developed and resulted in a 409 bp amplified fragment. The TK based PCR assay did not amplify the DNAs of other fish herpes viruses such as Herpesvirus cyprini (CHV) and the channel catfish virus (CCV). The TK based PCR assay was specific for the detection of KHV and was able to detect as little as 10 fentograms of KHV DNA corresponding to 30 virions. The TK based PCR was compared to previously described PCR assays and to viral culture in diseased fish and was shown to be the most sensitive method of diagnosis of KHV infection. CONCLUSIONS: The TK based PCR assay developed in this work was shown to be specific for the detection of KHV. The TK based PCR assay was more sensitive for the detection of KHV than previously described PCR assays; it was as sensitive as virus isolation which is the golden standard method for KHV diagnosis and was able to detect as little as 10 fentograms of KHV DNA corresponding to 30 virions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15774009&dopt=Abstract herpes medicine



herpes
Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses.

Christensen T.

Institute of Medical Microbiology and Immunology, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.

The hypothesis that human endogenous retroviruses (HERVs) play a role in autoimmune diseases is subject to increasing attention. HERVs represent both putative susceptibility genes and putative pathogenic viruses in the immune-mediated neurological disease multiple sclerosis (MS). Gammaretroviral HERV sequences are found in reverse transcriptase-positive virions produced by cultured mononuclear cells from MS patients, and they have been isolated from MS samples of plasma, serum and CSF, and characterised to some extent at the nucleotide, protein/enzyme, virion and immunogenic level.Two types of sequences, HERV-H and HERV-W, have been reported. No known HERV-H or HERV-W copy contains complete ORFs in all prerequisite genes, although several copies have coding potential, and several such sequences are specifically activated in MS, apparently resulting in the production of complete, competent virions. Increased antibody reactivity to specific Gammaretroviral HERV epitopes is found in MS serum and CSF, and cell-mediated immune responses have also been reported. Further, HERV-encoded proteins can have neuropathogenic effects.The activating factor(s) in the process resulting in protein or virion production may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS. Copyright (c) 2005 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15782388&dopt=Abstract herpes medicine



herpes
[Prevalence of Herpes simplex virus infection in pregnant women in Yopougon (Cote d'Ivoire)]

[Article in French]

Akoua-Koffi GC, Bakayoko S, Tanoh G, Tieoulou L, Angui H, Keita D, Faye-Kette H, Dosso M.

Laboratoire de bacteriologie-virologie, Faculte de medecine d'Abidjan et Institut Pasteur de Cote d'Ivoire.

A transversal survey on 150 pregnant women was carried out at the P.M.I. center in Yopougon, in order to determine the prevalence of genital herpes and to estimate the frequency of asymptomatic excreting of Herpes simplex virus (HSV) in pregnant women. The viral isolation and the direct immuno-fluorescence (IF) assay of the genital secretions were found to have a prevalence of 12.7% Among the women who tested positive (the majority of whom were from modest socio-economic origin and young), 10% had antecedents of genital herpes, 2.7% showed an asymptomatic excretion and 36.8% had an acute episode during their pregnancy including a primary infection in the 20th week. In these women an unexpected recurrence will constitute the major risk for maternal transmission and an emergence of neonatal herpes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10214509&dopt=Abstract herpes medicine



herpes
Comparison between virus isolation method, Papanicolaou stain, immunoperoxidase stain and polymerase chain reaction in the diagnosis of genital herpes.

Puthavathana P, Horthongkham N, Roongpisuthipong A, Maythangkul P, Kanyok R, Boonsirikhamchai P, Chaiyakul P.

Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Papanicolaou (Pap) stain, immunoperoxidase (IP) stain and polymerase chain reaction (PCR) were evaluated against the virus isolation method for their sensitivity and specificity in the diagnosis of herpes simplex virus (HSV) infection in 96 women who were suspected of genital herpes. The result showed that the sensitivity of PCR, IP and Pap stain was 100, 92.0 and 62.7%, respectively, while the specificity was 76.2, 66.7 and 81.0%, respectively. PCR was even more sensitive than the virus isolation technique. As Pap stain is the technique routinely performed for diagnosing genital herpes in most of the hospitals in Thailand, its low sensitivity should be taken into consideration. Based on the investigation by all four techniques together, HSV infection was diagnosed in 91.6% of the cases suspected of genital herpes which reflected higher precision of the clinical diagnosis over Pap stain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10219899&dopt=Abstract herpes medicine



herpes
Clinical course of patients with serologic evidence of recurrent genital herpes presenting with signs and symptoms of first episode disease.

Diamond C, Selke S, Ashley R, Benedetti J, Corey L.

Department of Medicine, University of Washington, Seattle, USA.

BACKGROUND AND OBJECTIVES: The care of patients with first episode and recurrent genital herpes differs with respect to therapy and source partner evaluation. Of 498 persons who presented with what appeared by history and symptoms to be a first episode of genital herpes, we identified 41 who had serologic evidence of remotely acquired herpes simplex virus 2 (HSV-2) infection. GOALS: To define the natural history of these individuals with previously unrecognized HSV-2 and to evaluate if any clinical or historical features could differentiate these people from persons with true first episode infection. STUDY DESIGN: Observational cohort study. RESULTS: Clinical overlap existed in the frequency of local symptoms, fever, and size of genital lesions between those with remotely acquired versus recently acquired genital herpes. The frequency of new sexual partners and recent sexual history were also similar in the two groups. However, on follow-up, the lesions of persons with remotely acquired HSV-2 healed more rapidly and subsequently recurred less frequently than those of true primary HSV-2. CONCLUSIONS: Even in a referral clinic with experienced clinicians, almost 10% of persons who are judged to have first episode genital herpes have evidence of remotely acquired HSV-2, suggesting that clinical differentiation of first episode genital herpes from previously acquired infection is difficult. Type-specific serologic testing assists the clinician in correctly classifying the infection and determining the potential source partner.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10225590&dopt=Abstract herpes medicine