herpes
Inhibition of herpes virus replication by a series of 4-oxo-dihydroquinolines with viral polymerase activity.

Hartline CB, Harden EA, Williams-Aziz SL, Kushner NL, Brideau RJ, Kern ER.

Department of Pediatrics, The University of Alabama School of Medicine, 128 CHB, 1600 6th Avenue South, Birmingham, AL 35233, USA.

Herpesviruses cause a wide variety of human diseases ranging from cold sores and genital herpes to encephalitis, congenital infections and lymphoproliferative diseases. These opportunistic viruses cause major problems in immunocompromised individuals such as transplant recipients, cancer patients, and HIV-infected persons. The current treatment of these infections is not optimal and there is a need for more active, less toxic compounds that might be used in place of or in addition to current therapies. We have evaluated a new series of 4-oxo-dihydroquinolines, which have a different mechanism of action than nucleosides and have activity against multiple herpes viruses. Of the four new compounds evaluated, two (PHA-529311 and PHA-570886) had greater activity than the parent, PHA-183792, against several herpes viruses and one (PHA-568561) was as effective as the parent. A fourth, PHA-243672, was considerably less effective. They had greater efficacy against cytomegalovirus (CMV) than the other herpes viruses tested and also had activity against acyclovir-resistant herpes simplex virus and varicella-zoster virus isolates and ganciclovir or foscarnet-resistant CMV isolates. These results confirm the broad-spectrum efficacy of these compounds against multiple herpes viruses and suggest that members of this class may have a potential role for treatment of a variety of herpes virus infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15708636&dopt=Abstract herpes medicine



herpes
The ectodomain of herpes simplex virus glycoprotein H contains a membrane alpha-helix with attributes of an internal fusion peptide, positionally conserved in the herpesviridae family.

Gianni T, Martelli PL, Casadio R, Campadelli-Fiume G.

Department of Experimental Pathology, Section on Microbiology and Virology, University of Bologna, Via San Giacomo, 12, 40126 Bologna, Italy.

Human herpes viruses enter cells by fusion with target membranes, a process that requires three conserved glycoproteins: gB, gH, and gL. How these glycoproteins execute fusion is unknown. Neural network bioinformatics predicted a membrane alpha-helix contained within the ectodomain of herpes simplex virus (HSV) gH, positionally conserved in the gH of all examined herpes viruses. Evidence that it has attributes of an internal fusion peptide rests on the following lines of evidence. (i) The predicted membrane alpha-helix has the attribute of a membrane segment, since it transformed a soluble form of gD into a membrane-bound gD. (ii) It represents a critical domain of gH. Its partial or entire deletion, or substitution of critical residues inhibited HSV infectivity and fusion in the cell-cell fusion assay. (iii) Its replacement with the fusion peptide from human immunodeficiency virus gp41 or from vesicular stomatitis virus G partially rescued HSV infectivity and cell-cell fusion. The corresponding antisense sequences did not. (iv) The predicted alpha-helix located in the varicella-zoster virus gH ectodomain can functionally substitute the native HSV gH membrane alpha-helix, suggesting a conserved function in the human herpes viruses. We conclude that HSV gH exhibits features typical of viral fusion glycoproteins and that this property is likely conserved in the Herpesviridae family.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15709012&dopt=Abstract herpes medicine



herpes
Is herpes zoster a marker for occult or subsequent malignancy?

Buntinx F, Wachana R, Bartholomeeusen S, Sweldens K, Geys H.

Department of General Practice, University of Leuven, Leuven, Belgium. Frank.buntinx med.kuleuven.ac.be

BACKGROUND: It has been suggested that herpes zoster may be a marker for occult malignancy. AIM: To examine the emergence of a subsequent cancer diagnosis in patients with and without herpes zoster. DESIGN OF STUDY: Retrospective cohort study. SETTING: Results were based on the database of Intego, an ongoing Belgian general practice-based morbidity registry, covering 37 general practitioners and including about 311 000 patient years between the years 1994 and 2000. METHOD: Survival analysis comparing the emergence of malignancy in patients with and without herpes zoster. RESULTS: The number of patients below the age of 65 years with herpes zoster, cancer or both was too low to draw any sensible conclusions. Above the age of 65 years we identified a significant increase of cancer emergence in the whole group and in females (hazard ratio = 2.65, 95% confidence interval = 1.43 to 4.90), but not in males. No difference could be identified in the first year after the herpes zoster infection. CONCLUSION: Our results do not justify extensive testing for cancer in herpes zoster patients. The association we identified, however, leaves open a number of questions with respect to the physiopathology behind it.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15720930&dopt=Abstract herpes medicine



herpes
In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpes virus replication.

Kern ER, Kushner NL, Hartline CB, Williams-Aziz SL, Harden EA, Zhou S, Zemlicka J, Prichard MN.

The University of Alabama at Birmingham, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Ave. South, Birmingham, AL 35233, USA. kern uab.edu

We have reported previously that methylenecyclopropane analogs of nucleosides have excellent activity against certain members of the herpes virus family. A second generation, the 2,2-bis-hydroxymethyl derivatives, were synthesized, and 18 compounds were tested for activity in vitro against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human and murine cytomegalovirus (HCMV and MCMV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Selected analogs were also evaluated against human herpes virus type 6 (HHV-6) and HHV-8. None of the 18 compounds had activity against HSV-1 or HSV-2, but four were active against VZV by plaque reduction (PR) assay at 50% effective concentration (EC(50)) levels of < or =50 microM. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC(50)s of 0.5 to 44 microM, and all were active against MCMV by PR (0.3 to 54 microM). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 microM). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 microM), and three compounds were active against HHV-8 (5.5 to 16 microM). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC(50)s of 0.7 to 8 microM. Toxicity was evaluated in adherent and nonadherent cells, and minimal cytotoxicity was observed. Mechanism of action studies with HCMV suggested that these compounds are phosphorylated by the ppUL97 phosphotransferase and are potent inhibitors of viral DNA synthesis. These results indicate that at least one of these compounds may have potential for use in treating CMV and other herpes virus infections in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728900&dopt=Abstract herpes medicine



herpes
Clinical spectrum of herpes zoster in HIV-infected versus non-HIV infected patients in Benin City, Nigeria.

Onunu AN, Uhunmwangho A.

Department of Medicine, University of Benin Teaching Hospital, Benin City, Nigeria.

BACKGROUND: Herpes zoster is due to reactivation of the varicella-zoster virus (VZV) at the sensory nerve ganglia. Some reports indicate that there might be differences in the pattern of presentation of herpes zoster in HIV infected patients. The objective of this study therefore, is to compare the clinical spectrum of herpes zoster in HIV-infected versus non-HIV infected patients. STUDY DESIGN: In this prospective study all patients presenting with clinical features of Herpes zoster had serological test (ELISA) for Human immunodeficiency viral (HIV) antibodies done and confirmed by the Double/Triple test algorithm. They were examined clinically to determine the dermatome(s) involved, the severity of the disease and the presence of any complication. The patients were categorized according to their HIV-status for the purpose of statistical analysis. RESULTS: Fifty-two out of the seventy-three patients seen during the study period were evaluated: 22 male (42.3 %) and 30 female (57.7 %) patients. Thirty-six (69.2 %) patients were HIV-positive while 16 (30.8%) were HIV-negative. The age distribution of the patients was bimodal; the mean age of patients in the HIV-positive group was 36.1+/-16.14 years while that of the HIV-negative group was 56.3+/-17.51 years. Multidermatomal involvement, affectation of the Trigeminal nerve dermatome and the presence of systemic symptoms such as fever and weakness correlated significantly with the presence of HIV infection. Mean times to cessation of new vesicle formation, crusting, and resolution of zoster-associated pain were also significantly longer in the HIV-positive patients. There were no statistically significant differences in the incidence of post-herpetic neuralgia, keloids, and bacterial super-infection in both groups. CONCLUSION: Herpes zoster was generally more severe in the presence of HIV infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15730088&dopt=Abstract herpes medicine



herpes
[Herpesvirus infection in patients with chronic glomerulonephritis]

[Article in Russian]

[No authors listed]

Virological examinations of blood, urine and saliva in 75 patients with chronic glomerulonephritis (CG) revealed, in 95% of them, herpes-virus infections caused by herpes simplex virus, type 1 (34.4%), herpes simplex virus, type 2 (2.6%) and cytomegalovirus (12%) or mixed infections (46%). The infection rate in the control group of children without renal pathology was reliably lower. A majority of CG patients (94%) had a diagnostically significant level of antiherpetic antibodies, class IgG, which also evidence to chronic herpes-virus infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15747870&dopt=Abstract herpes medicine



herpes
The Human Herpes Virus 8-Encoded Chemokine Receptor Is Required for Angioproliferation in a Murine Model of Kaposi's Sarcoma.

Jensen KK, Manfra DJ, Grisotto MG, Martin AP, Vassileva G, Kelley K, Schwartz TW, Lira SA.

Immunobiology Center and.

Kaposi's sarcoma (KS)-associated herpes virus or human herpes virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpes virus/human herpes virus 8 open reading frame 74 encodes a constitutively active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach for the treatment of KS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15749907&dopt=Abstract herpes medicine



herpes
Characterization of T-cell reactive epitopes in glycoprotein G of herpes simplex virus type 2 using synthetic peptides.

Bellner L, Lowhagen GB, Tunback P, Nordstrom I, Liljeqvist JA, Eriksson K.

Department of Rheumatology and Inflammation Research, Goteborg University, Goteborg, Sweden.

We have previously shown that the CD4+ T-cell response to herpes simplex virus type 2 glycoprotein G-2 is type-specific and can thus be used to evaluate herpes simplex virus type 2-specific T-cell responses in individuals with a concomitant herpes simplex virus type 1 infection. In this study we have followed the glycoprotein G-2-specific T-cell responses over time, and also tried to identify T-cell epitopes in the membrane bound portion and the secreted portion of glycoprotein G-2 using synthetic peptides spanning the whole amino acid sequence of glycoprotein G-2. We found that the magnitude of the glycoprotein G-2-specific response varied considerably in infected individuals over time, even though all patients responded to at least one of the two glycoproteins at all time-points examined. We could also document strong T-cell responses to synthetic peptides from the secreted glycoprotein G-2 but only low responses to synthetic peptides corresponding to sequences from the heavily glycosylated membrane-bound glycoprotein G-2. We were able to map an immunogenic region (amino acid 31-125) within the secreted glycoprotein G-2. This region of the glycoprotein induced proliferative responses in 47% of the herpes simplex virus type 2-infected individuals. However, we were not able to identify any universal T-cell epitope.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15750862&dopt=Abstract herpes medicine