Herpesviruses 2000: Update 2000

Shittitoe, Gilchrist, Pellena, Murrah. "Effects of Herpes Simplex Virus on Human Oral Cancer Cells, and Potential Use of Mutant Viruses in Therapy of Oral Cancer." Oral Oncology. May 1999. 35(3):326-332.

This study was done to determine whether HSV-1 could be used as a beneficial agent in oral carcinomas. Since HSV-1 has an affinity for the cells of the oropharynx by nature, this was thought to be a good virus to use. A gene necessary for the virus' replication (UL42) was deleted to prevent the virus from spreading through the body.

The results of the study seem quite encouraging. The virus inhibits cancer cells by activating ganciclovir in the malignant cells. The only problem was that even the "inactivated" viruses still seemed to have some neurotoxicity. The research team suggested that a mutant be developed that had a promotor on UL42 that will only work in cancer cells. This way the virus can replicate and spread through an oral tumor with minimal effects on the rest of the body.

Bonnet; et al. "Detection of Epstein-Barr Virus in Invasive Breast Cancer." Journal of the National Cancer Institute. August 1999. 91(16):1376-1381.

In a study of 100 samples of primary breast cancer carcinomas, Epstein-Barr virus was found in 51% of them. While this in and of itself may not seem amazing because approximately 90% of adults have been infected with EBV at some point, this is unusual in light of the fact that EBV was found in the surrounding tissue in only 10% of the patients. EBV was also more likely to be found in samples from the most aggressive carcinomas.

The research team do not suggest that EBV causes breast cancer or that it is even necessary for breast cancer, but there does seem to be the possibility that EBV could be a cofactor in some cases.

Niedobitek, Gerald. "Epstein-Barr virus: a group 1 carcinogen?" Virchows Archive. August 1999. 453(2):79-86

This article reviews the data regarding the oncogenic potential of EBV shortly after it was declared a group 1 carcinogen by the World Health Organization. Agents in group 1 are those that are definitely considered to be carcinogenic to humans.

The author of this paper seems to feel that the evidence for the oncogenic effects of EBV is very strong. He notes specifically the case of nasopharyngeal carcinoma a tumor that has never been found to not contain EBV. Another compelling example comes from the case of post-transplantation lymphoproliferative disorders which recede rapidly once immunity to EBV has again been established.

This article sums up well all the recent discoveries that have been made regarding EBV as a carcinogen. Anyone interested in more detail should see the article.

Gurtsevich, VE; et al. "Detection and Characterization of Gastric Carcinoma Associated with Epstein-Barr Herpes Virus." Vestnik Rossiiskoi Akademii Meditsinskikh Nauk. 1999. 3:56-9.

In this Russian study, 184 samples of gastric carcinoma were examined for the presence of Epstein-Barr virus. Only 17 of the samples (9.24%) showed uniform infection. Infection of the samples was shown to be more common in males as well as in less differentiated tumors located in the upper stomach.

While this data is not particularly compelling if one has the hypothesis that EBV causes gastric carcinoma, this could be considered evidence for possible cofactor activity.

Persing and Prendergast. "Infection, Immunity, and Cancer." Archives of Pathology and Laboratory Medicine. November 1999. 123(11):1015-1022.

This article contained a lot of information regarding pathogenesis of several cancers thought to be caused by Herpesviruses.

In Burkitt lymphoma (which is caused by Epstein-Barr virus), it has been determined that the pathogenesis of these carcinomas involved gene rearrangement. During infection, there is the possibility that the ends of certain chromosomes may break off and reattach on different chromosomes. Cancer is caused in the case when an oncogene (c-myc) breaks off and becomes reattached downstream from the cell's IgG promoter. Since Burkitt, in his original studies of Burkitt lymphoma, determined that the highest incidence of this disease in Africa occurred within the malaria belt, it has been postulated that the cancer may occur when the body steps up its IgG production to fight malaria. As the IgG promoter becomes more active, more and more of the oncogenic product is made, which may eventually result in cancer.

Chromosomally integrated HHV-6

Daibata M, Taguchi, T, Nemoto Y, Taguchi H, and Miyoshi I. "Inheritance of chromosomally integrated human herpesvirus 6 DNA." Blood. 1999 Sept 1;94(5):1545-9.

Human herpesvirus 6 (HHV-6) genome has been found integrated in the chromosomes of some people with human lymphoproliferative disorders. This report focuses on a woman with Burkitt?s limphoma who has HHV-6 integration on her chromosome 22, a man with HHV-6 integration on his chromosome 1, and their daughter who has HHV-6 integration at both points in her blood cell DNA. All three of them were seropositive when tested for HHV-6 with no signs of active infection. This evidence was used to hypothesize a novel latent form of HHV-6, in which integrated viral DNA can be chromosomally transmitted.

Reply:

Hermouet, S, Minvielle, S. "Inheritance of chromosomally integrated viral DNA?" Blood. 2000 Feb 1;95(3):1108-9.

A letter to the editor proposes that the daughter could have acquired her integrated viral DNA during an intrauterine viral transmission with her mother's virus which would integrate on chromosome 22 and then caught her father's virus which would integrate on chromosome 1. They suggest that Daibata should use FISH analysis to show that all of the daughter's cells show this pattern because all her cells were inherited. The other possibility is that only her blood cells have the integration because of intrauterine or horizontal transmission of virus.

A new test for resistant strains of HSV

Cotarelo, M, et al. "Cytopathic effect inhibition assay for determining the in-vitro susceptibility of herpes simplex virus to antiviral agents." Journal of Antimicrobial Chemotherapy. 1999 Nov; 44(5):705-708.

Since treatment with acyclovir or foscarnet is only effective when the virus strain being treated is not resistant to these drugs, a test that could quickly and cheaply test for resistance is in high demand. Up to this point, the test most often used, plaque reduction assay (PRA), takes about 5-7 days to process. A new test being proposed by this study would take 3 days to reach a conclusion. The test works by isolating virus from the patient, inoculating it on cells growing in culture, and performing dilutions with no viral agent, acyclovir, and foscarnet. The cells are then allowed to grow and the virus to replicate. Then the cultures are looked at under the microscope for cytopathic effect (CPE). If CPE is present in the cultures diluted with the drugs, they are resistant and a different form of action can be taken. This test will be very useful to check for resistant strains of herpesvirus and potentially any virus with a visible CPE.

Dr. Siegel's RAU hypothesis: fact or fiction?

Brice, SL, Cook, D, Leahy, M, Huff, JC, and Weston, WL. "Examination of the oral mucosa and peripheral blood cells of patients with recurrent aphthous ulceration for human herpesvirus DNA." Oral Surgery Oral Medicine Oral Pathology Radiology Endocrinology. 2000 Feb;89(2):193-8.

To test Dr. Siegel's hypothesis that recurrent aphthous ulceration (RAU) could be caused by the recurrence of a herpesvirus, Brice et al. tested patients with and without RAU for the presence of human herpesvirus DNA in their oral mucosa and peripheral blood cells. Their results showed higher levels of herpes simplex virus and human herpesvirus from the control subjects than the RAU subjects. There was no difference between the two groups of levels of the rest of the herpesviruses. Their conclusion is that the deterction of human herpesvirus DNA from the oral mucosa and peripheral blood cells of patients with RAU represents normal viral shedding and not a direct causal mechanism in these cases.

Mechanisms of EBV Latency

Prang, N, Wolf, H, and Schwarzmann, F. "Latency of Epstein-Barr virus is stabilized by antisense-mediated control of the viral immediate-early gene BZLF-1." Journal of Medical Virology. 1999 Dec;59(4):512-9.

Herpesviruses have the unique feature of latency. They are able to infect neurons and live there and then reappear as recurrent infections later on. This paper attempts to elucidate the mechanism for Epstein-Barr virus (EBV) latency. Primarily EBV establishes latency in B-lymphocytes. The gene they looked at specifically is called BZLF-1, whose protein product is important in the induction of lytic replication. They showed that BZLF-1 mRNA is present in latent infections, but that it is not making a protein product. Since the cells are not making this protein, they do not have lytic replication and are not producing infections. This is regulated by a strand of RNA that complements the region to keep BZLF-1 from being translated. This post-translational control appears to be a back-up control mechanism in addition to transcriptional regulation in stabilizing latency.

DiFrancesco, P, Lisi, A, Rieti, S, Manni, V, Grimaldi, S and Garaci, E. "Cocaine potentiates the switch between latency and replication of Epstein-Barr virus in Raji cells." Biochemistry Biophysical Research Communications. 1999 Oct 14;264(1):33-6.

Co-factors such as drug-use, malnutrition and co-infection with other viruses can influence the duration, severity, and complications of a viral infection This paper looks at the way cocaine effects the course of Epstein-Barr virus (EBV). In particular, the authors were interested in determining cocaine's effect on cells housing a latent infection of EBV. After adding cocaine to Raji cells in a cell culture, they discovered that there was an increase in Ca (+2) mobilization and induction of cellular protein phosphorylation. The cells also showed induction of a protein called ZEBRA which is responsible for the activation of early viral genes necessary for the virus to enter lytic replication. This result implies that cocaine is a co-factor in recurrent infection of EBV.

Bonnet; et al. "Detection of Epstein-Barr Virus in Invasive Breast Cancer." Journal of the National Cancer Institute. August 1999. 91(16):1376-1381.

Brice, SL, Cook, D, Leahy, M, Huff, JC, and Weston, WL. "Examination of the oral mucosa and peripheral blood cells of patients with recurrent aphthous ulceration for human herpesvirus DNA." Oral Surgery Oral Medicine Oral Pathology Radiology Endocrinology. 2000 Feb;89(2):193-8

Cotarelo, M, et al. "Cytopathic effect inhibition assay for determining the in-vitro susceptibility of herpes simplex virus to antiviral agents." Journal of Antimicrobial Chemotherapy. 1999 Nov; 44(5):705-708.

Daibata M, Taguchi, T, Nemoto Y, Taguchi H, and Miyoshi I. "Inheritance of chromosomally integrated human herpesvirus 6 DNA." Blood. 1999 Sept 1;94(5):1545-9.

Flint et al. Principles of Virology: Molecular Biology, Pathogenesis, and Control. Washington D.C.:ASM Press, 2000.

Hermouet, S, Minvielle, S. "Inheritance of chromosomally integrated viral DNA?" Blood. 2000 Feb 1;95(3):1108-9.

Gurtsevich, VE; et al. "Detection and Characterization of Gastric Carcinoma Associated with Epstein-Barr Herpes Virus." Vestnik Rossiiskoi Akademii Meditsinskikh Nauk. 1999. 3:56-9.

Niedobitek, Gerald. "Epstein-Barr virus: a group 1 carcinogen?" Virchows Archive. August 1999. 453(2):79-86

Persing and Prendergast. "Infection, Immunity, and Cancer." Archives of Pathology and Laboratory Medicine. November 1999. 123(11):1015-1022.

Sacks SL, Wilson B. "Famciclovir/penciclovir." Advances in Experimental Medical Biology. 1999; 458: 135-147.

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Created: March 1st, 2000
Updated: March 5th, 2000