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Biomedical subjects

D V Ablashi

Publications and source records attributed to D V Ablashi.

At least 37 records · Page 2Linked to original sources
PubMed1995

Human herpesvirus-7 (HHV-7): current status.

BACKGROUND: Human herpesvirus-7 (HHV-7) is a newly discovered virus and very little is known about its prevalence, biologic, immunologic and molecular biology aspect. Besides the HHV-7 etiologic role in a few cases of exanthem subitum, its association with other diseases has not been reported. OBJECTIVES: To review what is currently known about HHV-7. RESULTS: HHV-7 was first isolated in 1990 from purified T-cells from a healthy individual. Following this report, an independent isolation of HHV-7 was reported from the mononuclear cells (PBMC) of a chronic fatigue syndrome patient. HHV-7 is closely related to human herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV), but is distinct from Epstein-Barr virus (EBV), herpes simplex virus and varicella zoster virus. Using polyvalent and monoclonal antibodies, several HHV-7 viral proteins were identified, ranging from 136 to 30 kDa. HHV-7 infection occurs later than HHV-6, which appears in early childhood. HHV-7 is ubiquitous, and its prevalence rate is >85% in the US population, although its rates of prevalence in Japan is lower than in the USA and Europe. HHV-7 is frequently isolated from saliva; however, HHV-7 has been consistently isolated from PBMC from young children as well. Several cases of exanthem subitum have been linked to primary infection of HHV-7, suggesting that it may also cause exanthem subitum. Primary infection with HHV-7 was also reported from a patient with features of hepatitis and exanthem subitum. This virus was also isolated from tissues from a case of hepatosplenomegaly and pancytopenia lacking either EBV or HCMV. Thus far, no other disease associated with HHV-7 has been reported. Only one continuous T-cell line (SupT1) can support the replication of HHV-7, but the virus yield is extremely low. CONCLUSIONS: It has been about 4 years since this member of the human herpesvirus family was reported. In the coming years, more data will be available on the epidemiology, biology, immunology, molecular biology, and pathogenesis of HHV-7. The finding of reciprocal interference between HHV-7 and HIV-1, suggesting competition at the receptor level is important, needs further work and here HHV-7 may play a role as a negative cofactor in the natural history of HIV infection. Because of HHV-7 interaction with HIV-1, the possibility of its vertical transmission needs to be investigated. This review on HHV-7 is intended to provide current information on HHV-7.

Journal Article↗
PubMed1995

Human herpesvirus 6 as a potential copathogen.

The molecular, biological and immunological studies of the recently identified human herpesvirus 6 (HHV-6) suggest that the virus is involved in the etiology of at least three lymphoproliferative diseases. Furthermore, HHV-6 may be an important cofactor in the pathogenesis of several other diseases, including HIV-associated disease and some cancers, but further investigation is needed to establish a causal relationship.

Acquired Immunodeficiency Syndrome↗
PubMed1995

HIV-1 and HHV-6 antigens and transcripts in retinas of patients with AIDS in the absence of human cytomegalovirus.

PURPOSE: The purpose of this study was to define the agents involved in the development of acquired immune deficiency syndrome (AIDS)-associated retinitis. To achieve this goal, the authors determined the frequency and proximity of the simultaneous presence of human immunodeficiency virus (HIV)-1, human herpesvirus (HHV)-6, and human cytomegalovirus (HCMV) in retinas of patients with AIDS with and without AIDS-associated retinitis. METHODS: Retinal sections from 50 globes from patients with AIDS were analyzed for the presence of viral antigens and transcripts. Group 1 contained 13 globes from patients with HCMV infection. Group 2 contained 20 globes from patients with retinal lesions of uncertain etiology in which HCMV antigen and transcripts were not detected. Group 3 contained 17 globes from patients with no retinal lesions. RESULTS: Retinal sections from all 13 globes (group 1) were positive for HCMV antigens and HIV-1 antigens and transcripts. Six of the 13 retinas were also positive for HHV-6 antigens and transcripts. Sections from 13 of the 20 globes (group 2) were positive for HIV-1 antigens and transcripts, and 5 of these 13 were also positive for HHV-6 antigens and transcripts. Multiple areas in sections from two of the HIV-1-positive retinas showed coinfection with HHV-6. All 17 globes (group 3) were positive for HIV-1 antigens and transcripts. Ten of these 17 retinas were also positive for HHV-6 antigens. Human cytomegalovirus antigens were not detectable in retinas from groups 2 and 3. No viral antigens or transcripts were detectable in retinal sections from 10 HIV-1 negative donors. CONCLUSION: The coexistence of HIV-1 and HHV-6 activity in more than 50% of retinas without HCMV infection suggests that HIV-1 and HHV-6 alone or in combination may predispose retinal tissue to other opportunistic agents such as HCMV during the development of AIDS-associated retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Multistage carcinogenesis utilizing human genital cells and human papillomaviruses.

The preponderance of evidence indicates that a subset of human papillomaviruses are important etiological agents for cervical cancer. However, the necessity of other agents as well as cellular events is recognized because not all women with papillomaviruses develop cancer. Therefore, the exact role of papillomaviruses in the multistage carcinogenesis process is unclear. Regulation of specific viral genes is important to the malignant process. The current study demonstrates that human herpesvirus-6, another ubiquitous virus, can infect genital epithelial cells and upregulate the expression of relevant papillomavirus genes. Thus, it can be considered a cofactor for cancer.

Antibodies, Monoclonal↗
PubMed1994

Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome.

Levels of 2',5'-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls. Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6). Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

2',5'-Oligoadenylate Synthetase↗
PubMed1994

Human herpesvirus 6 infects cervical epithelial cells and transactivates human papillomavirus gene expression.

To examine whether human herpesvirus 6 (HHV-6) is capable of infecting human cervical epithelial cells and altering expression of human papillomavirus (HPV) genes, HPV-immortalized or -transformed carcinoma cell lines were infected with HHV-6 variant A. No cytopathic effect was observed in infected cervical cells. However, immunofluorescence indicated that infected cells expressed early-late proteins of HHV-6 by day 3 postinfection. HHV-6 DNA was also detected by Southern blot hybridization after infection and persisted through continued subculture in an episomal state as proven by Gardella gel electrophoresis and fluorescence in situ hybridization. HHV-6 infection enhanced expression of HPV RNAs encoding the viral oncoproteins E6 and E7. Transient transfection assays showed that two HHV-6 molecular clones, pZVB-70 and pZVH-14, upregulated transcription 9- to 15-fold from a receptor plasmid containing the HPV type 18 regulatory sequences which control transcription in vivo. Cervical carcinoma cells infected with HHV-6 induced more rapid development of tumors in mice than did noninfected cells. These results are the first evidence that human cervical epithelial cells can be infected with HHV-6 and that HHV-6 contains transactivators which stimulate the HPV-transforming genes.

Animals↗
PubMed1993

Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6.

One common attribute of herpesviruses is the ability to establish latent, life-long infections. The role of virus-virus interaction in viral reactivation between or among herpesviruses has not been studied. Preliminary experiments in our laboratory had indicated that infection of Epstein-Barr virus (EBV) genome-positive human lymphoid cell lines with human herpesvirus 6 (HHV-6) results in EBV reactivation in these cells. To further our knowledge of this complex phenomenon, we investigated the effect of HHV-6 infection on expression of the viral lytic cycle proteins of EBV. Our results indicate that HHV-6 upregulates, by up to 10-fold, expression of the immediate-early Zebra antigen and the diffuse and restricted (85 kDa) early antigens (EA-D and EA-R, respectively) in both EBV producer and nonproducer cell lines (i.e., P3HR1, Akata, and Raji). Maximal EA-D induction was observed at 72 h post-HHV-6 infection. Furthermore, expression of late EBV gene products, namely, the viral capsid antigen (125 kDa) and viral membrane glycoprotein gp350, was also increased in EBV producer cells (P3HR1 and Akata) following infection by HHV-6. By using dual-color membrane immunofluorescence, it was found that most of the cells expressing viral membrane glycoprotein gp350 were also positive for HHV-6 antigens, suggesting a direct effect of HHV-6 replication on induction of the EBV replicative cycle. No expression of late EBV antigens was observed in Raji cells following infection by HHV-6, implying a lack of functional complementation between the deleted form of EBV found in Raji cells and the superinfecting HHV-6. The susceptibility of the cell lines to infection by HHV-6 correlated with increased expression of various EBV proteins in that B95-8 cells, which are not susceptible to HHV-6 infection, did not show an increase in expression of EBV antigens following treatment with HHV-6. Moreover, UV light-irradiated or heat-inactivated HHV-6 had no upregulating effect on the Zebra antigen or EA-D in Raji cells, indicating that infectious virus is required for the observed effects of HHV-6 on these EBV products. These results show that HHV-6, another lymphotropic human herpesvirus, can activate EBV replication and may thus contribute to the pathogenesis of EBV-associated diseases.

Antigens, Viral↗
PubMed1992

Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus.

An independent strain (JI) of human herpesvirus 7 (HHV-7) was isolated from a patient with chronic fatigue syndrome (CFS). No significant association could be established by seroepidemiology between HHV-7 and CFS. HHV-7 is a T-lymphotropic virus, infecting CD4+ and CD8+ primary lymphocytes. HHV-7 can also infect SUP-T1, an immature T-cell line, with variable success. Southern blot analysis with DNA probes scanning 58.8% of the human herpesvirus 6 (HHV-6) genome and hybridizing to all HHV-6 strains tested so far revealed homology to HHV-7 with only 37.4% of the total probe length. HHV-7 contains the GGGTTA repetitive sequence, as do HHV-6 and Marek's disease chicken herpesvirus. DNA sequencing of a 186-base-pair fragment of HHV-7(JI) revealed an identity with HHV-6 and human cytomegalovirus of 57.5% and 36%, respectively. Oligonucleotide primers derived from this sequence (HV7/HV8, HV10/HV11) amplified HHV-7 DNA only and did not amplify DNA from other human herpesviruses, including 12 different HHV-6 strains. Southern blot analysis with the p43L3 probe containing the 186-base-pair HHV-7 DNA fragment hybridized to HHV-7 DNA only. The molecular divergence between human cytomegalovirus, on the one hand, and HHV-6 and HHV-7, on the other, is greater than between HHV-6 and HHV-7, which, in turn, is greater than the difference between HHV-6 strains. This study supports the classification of HHV-7 as an additional member of the human beta-herpesviruses.

Amino Acid Sequence↗
PubMed1992

Modulatory effects of Epstein-Barr, herpes simplex, and human herpes-6 viral infections and coinfections on cytokine synthesis. A comparative study.

Herpesviruses such as EBV, HSV, and human herpes virus-6 (HHV-6) have a marked tropism for cells of the immune system and therefore infection by these viruses may result in alterations of immune functions, leading at times to a state of immunosuppression. We report the results of a comparative study in which we found that EBV, HSV-1, and HHV-6 act differentially on the immune system with regard to their effect on the synthesis of IL-1 beta, IL-6, and TNF-alpha, i.e., three immunoregulatory cytokines mainly secreted by activated monocytes/macrophages. Using the polymerase chain reaction technique, analyses of the mRNA levels for each of the three monokines after viral infection indicated that the effect exerted by each of these herpesviruses on cytokine synthesis by human PBMC was detectable at the transcriptional level. Different amounts of IL-1 beta protein were detected in infected PBMC cultures, HHV-6 being the strongest IL-1 beta up-regulatory among these three herpesviruses. Spontaneous releases of IL-6 and TNF-alpha were found reduced after infection by HHV-6 and EBV, respectively. In comparison to EBV and HHV-6, HSV-1 proved to be a weak monokine enhancer. Results of coinfection studies indicated that virus-induced suppressive effects on cytokine synthesis are dominant. In fact, EBV inhibited TNF-alpha synthesis even in the presence of HHV-6, a strong up-regulator of TNF-alpha synthesis. Similarly, EBV was unable to stimulate IL-6 production in the presence of HHV-6. Viral structural component(s) appeared to be responsible for the up-regulation of IL-6 by both EBV and HSV-1, and of TNF-alpha by HSV-1. Taken together, our observations illustrate that herpesviruses can selectively regulate cytokine synthesis thereby disturbing immune homeostasis; this effect may favor pathogenic events, including the reactivation and/or spread of other infectious agents within the host.

Base Sequence↗
PubMed1992

Antibodies to human herpes virus-6 and clinical course in patients with Hodgkin's disease.

Serial serum samples from 37 patients with Hodgkin's disease (HD) and 39 healthy controls were studied for antibodies to human herpes virus-6 (HHV-6) using ELISA and indirect immunofluorescent antibody (IFA) tests and to the Epstein-Barr virus (EBV) using a radio-complement fixation assay. Antibodies to HHV-6 in the pre-treatment sera from the HD patients were not significantly different from those of controls, but significant changes in titers related to clinical course were noted among the HD patients. HHV-6 IFA titers increased significantly in the course of follow-up in patients who relapsed and decreased significantly over time in patients who did not. These serologic studies support tissue-based investigations indicating that EBV plays a greater etiologic role in HD than HHV-6, although HHV-6 serology may be of prognostic value or may assist in identifying individuals with immunologic abnormalities. The identification of diverse HHV-6 antibody patterns using different assays may reflect the presence of a number of antibodies with varying implications, similar to those identified for EBV.

Adolescent↗
PubMed1992

Antigenic relationships among human herpesvirus-6 isolates.

Human herpesvirus 6 (HHV-6) prototype isolate GS is a newly identified lymphotropic herpesvirus and several subsequent herpes isolates were recognized as HHV-6 by their hybridization to a HHV-6(GS) DNA probe pZVH14. DNA restriction analysis and in vitro tropism studies show that HHV-6 isolates can be divided into two groups, designated group A and group B. Antigenic relationships among 15 HHV-6 isolates belonging to these two groups were examined using rabbit antibodies against HHV-6(GS) infected cells, 11 monoclonal antibodies against three glycoproteins and four non-glycoproteins of HHV-6(GS), and sera from 136 healthy adults. More than 20 polypeptides from all these isolates were immunoprecipitated by rabbit polyclonal antibodies against HHV-6(GS) infected cells. Reactivities of monoclonal antibodies segregated these isolates into the same two groups. Group A contains HHV-6(GS), HHV-6(U1102) from a Ugandan acquired immunodeficiency syndrome (AIDS) patient, and nine other HHV-6 isolates from various disorders. HHV-6(Z-29) from a Zairian AIDS patient, HHV-6(SF) isolated from the saliva of a human immunodeficiency virus (HIV)-infected individual, HHV-6(OK) from a child with exanthem subitum, and HHV-6(DC) from a leukopenia patient are in group B. Eighty-one percent of the sera showed similar antibody titer in immunofluorescence assay with group A HHV-6(GS) and group B HHV-6(Z-29) infected cells and 19% of the sera showed two- to four-fold antibody titer differences. The mobilities of many of the polypeptides immunoprecipitated from group A HHV-6(GS) and group B HHV-6(Z-29) infected cells were different and sera showed differences in the quantities and nature of polypeptides immunoprecipitated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Infection by human herpesvirus 6 (HHV-6) of human lymphoid T cells occurs through an endocytic pathway.

We have analyzed by immunoelectron microscopy the early events of binding and internalization of human herpesvirus 6 (HHV-6, strain GS) on a susceptible T-lymphoblastoid cell line, HSB-2. The virions bound to the cell surface at 4 degrees C were tightly associated with the plasma membrane. Gold immunolabeling of the viral envelope proteins was strong and specific. Warming at 37 degrees C for different times showed viral internalization through smooth surfaced pits and vesicles. Fusion events of the virions with the cell plasma membrane were never observed. Gold immunolabeling performed in parallel experiments before or after viral internalization showed: (1) absence of viral envelope proteins on the cell plasma membranes at all times of internalization, again excluding fusion events; (2) entry of the virions with their envelopes. Treatment of the cells with chloroquine, a drug known to affect the endocytic pathway, led to an almost complete inhibition of viral infectivity, suggesting that the endocytosed virions are responsible for a successful infection. Comparable results were obtained using a second strain of HHV-6 (BA92), with biologic and molecular characteristics similar to the prototype strain Z29. The chloroquine inhibition was effective on two different T cell lines (HSB-2 and J-Jhan), as well as on phytohemagglutinin-stimulated peripheral blood mononuclear cells.

Cell Line↗