Air pollution is a serious health problem in major cities in Mexico. The concentrations of monito... more Air pollution is a serious health problem in major cities in Mexico. The concentrations of monitored criteria pollutants have been above the US National Ambient Air Quality Standards for the last decade. To determine whether the number of primary malignant nasal and paranasal neoplasms has increased, we surveyed 256 such cases admitted to a major adult oncology hospital located in metropolitan Mexico City (MMC) for the period from 1976–1997 and to a tertiary hospital in Monterrey, an industrial city, for the period from 1993–1998. The clinical histories and histopathologic material were reviewed, and a brief clinical summary was written for each case. In the MMC hospital the number of newly diagnosed nasal and paranasal neoplasms per year for the period from 1976–1986 averaged 5.1, whereas for the next 11 years it increased to 12.5. The maximal increase was observed in 1995–1997, with an average of 20.3 new cases per year ( P = 0.0006). The predominant neoplasms in these series were...
Journal of the American Academy of Dermatology, 1989
To compare the therapeutic effects of surgical excision and orally administered acyclovir therapy... more To compare the therapeutic effects of surgical excision and orally administered acyclovir therapy on symptomatic oral hairy leukoplakia, 45 homosexual men who were seropositive for human immunodeficiency virus participated in a 3-month open-label study. In the 14 patients who had surgical excision, pain resolved in four symptomatic patients and the leukoplakia did not recur in the areas of excision. New foci of leukoplakia, however, appeared in 10 patients after 3 months. Of the 16 patients who received acyclovir therapy, 12 had a clinical regression, although recurrences were noted in all patients after 3 months. Three patients had resolution of pain while taking acyclovir; in two the pain recurred after acyclovir was discontinued. No spontaneous remissions of the leukoplakia occurred in the 15 patients who refused therapy. We conclude that surgical excision is effective in patients with symptomatic oral hairy leukoplakia.
Epstein-Barr virus (EBV) is associated with lymphomas and lymphoproliferative diseases that occur... more Epstein-Barr virus (EBV) is associated with lymphomas and lymphoproliferative diseases that occur mainly in immunocompromised patients, but the role EBV plays in their pathogenesis is unclear. The evidence linking EBV etiologically to these disorders includes the presence of EBV DNA and nuclear antigens in the lesions and serologic evidence that some patients with these lesions are experiencing primary or reactivated EBV infections. These syndromes may represent proliferation of cells latently infected with EBV, but the possibility of viral replication has not been rigorously studied. DNA extracted from biopsies of 35 lymphoproliferative diseases was probed with regions of the EBV genome capable of distinguishing circular, episomal DNA found in latency from linear, replicating EBV DNA. All samples contained restriction fragments characteristic of fused termini, indicative of circular, latent genomes. Thirteen samples contained additional restriction fragments diagnostic of linear EBV DNA. Therefore, replicating EBV DNA is found in approximately 40% of EBV-associated lymphoproliferative disorders.
By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enable... more By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enables Abs to acquire new effector functions that are crucial for the neutralization of invading pathogens. Class switching occurs through class switch DNA recombination (CSR) and usually requires engagement of CD40 on B cells by CD40 ligand on Ag-activated CD4+ T cells. CSR must be tightly regulated because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by EBV infection. In this study, we show that EBV induces CD40-independent CSR from Cμ to multiple downstream Cγ, Cα, and Cε genes through latent membrane protein 1 (LMP1), a CD40-like viral protein that signals in a ligand-independent fashion. LMP1-induced CSR is associated with transcriptional activation of germline Cγ, Cα, and Cε genes and triggers the up-regulation of activation-induced cytidine deaminase, a c...
A JB6 mouse epidermal recipient cell line has been used to detect nasopharyngeal carcinoma (NPC) ... more A JB6 mouse epidermal recipient cell line has been used to detect nasopharyngeal carcinoma (NPC) DNA-associated transforming activity that is not detectable in the NIH 3T3 focus assay. NPC DNA showed both transforming activity and activity for transferring sensitivity to tumor-promoterinduced neoplastic transformation, assayed in 2 different variants of mouse JB6 cells. Comparison of DNAs from various NPC sources that did or did not harbor EBV DNA and that varied in degree of differentiation showed similar transforming activities and similar activities for transferring promotion sensitivity. Thus both a NPC DNA-associated promotion sensitivity and an oncogenic activity function independently of concurrent EBV gene expression. 'To whom reprints should be addressed.
Acute mononucleosis rarely is associated with inflammatory arthritis. Although some patients with... more Acute mononucleosis rarely is associated with inflammatory arthritis. Although some patients with acute Epstein-Barr virus infection complain of arthralgia, only 4 patients with associated inflammatory synovitis have been reported (1,2). We report a patient with acute Epstein-Barr virus infection who had associated monoarticular inflammatory knee arthritis. Genomic analysis of Epstein-Barr virus from synovial fluid illustrated a reactive arthritis, rather than replication of Epstein-Barr virus.
This report describes the results of histopathologic and virologic studies in six patients with u... more This report describes the results of histopathologic and virologic studies in six patients with undifferentiated carcinoma (malignant lymphoepithelial lesions) of the salivary glands. Epstein-Barr virus (EBV) was detected in tumors from all six patients by DNA hybridization, while adjacent non-tumorous salivary gland tissue was negative for EBV in two patients tested for DNA and in three patients tested for Epstein-Barr nuclear antigen (EBNA). These findings add more evidence that these unusual salivary gland tumors are EBV-associated, and that EBV is specific to the tumor.
Recent studies have identified several EBV-specific transcripts in C15, an NPC passaged in nude m... more Recent studies have identified several EBV-specific transcripts in C15, an NPC passaged in nude mice1,2. These transcripts include both of the EBER RNAs, two related transcripts encoding LMP and several RNAs transcribed rightward from BamHI A3. Early replicative messages were not detected in C15, suggesting that this tumor is latently infected; therefore, the viral RNAs expressed from BamHI A are latent transcripts. The detection of transcription from BamHI A in latently infected epithelial cells is interesting because this region has not previously been identified as being transcriptionally active in latently infected lymphoid cells either by Northern blot or in situ hybridization4,5. This study investigates whether transcription from BamHI A is a consistent feature in NPC and attempts to determine whether these RNAs could possibly encode one or more viral antigens which are expressed in NPC.
A novel strain of Epstein-Barr virus (EBV) has been isolated from a young girl (SA) and her fathe... more A novel strain of Epstein-Barr virus (EBV) has been isolated from a young girl (SA) and her father both suffering from chronic active EBV infection (1). Selected throat washings from these patients induced the early antigen (EA) in Raji cells, observed using indirect immunofluorescence with polyvalent human antisera. Moreover, unlike virtually all natural EBV isolates, these throat washings never transformed cord blood leukocytes in a total of over 24 trials. Our previous experimental results also attest to the failure encountered in attempting to establish spontaneous lymphoblastoid cell lines (LCLs) from the peripheral blood of these patients. However, a spontaneous LCL was obtained from the mother of SA. Cell lines were only established by B95–8 induction and not without extreme difficulty. In fact, we were only able to obtain 3 B95–8-induced LCLs from the girl in approximately 30 trials, 2 of which were established in the presence of cyclosporin A.
Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aet... more Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aetiological agents of HIV-associated oral lesions. Oral lesions common to the early phase of the AIDS epidemic, including Kaposi's sarcoma (KS), oral aphthous ulceration, AIDS-associated oral lymphoma, and oral hairy leukoplakia (OHL), have been tested for the prevalence of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). While EBV DNA is detected by PCR in all of these lesions, abundant viral replication can only be detected in OHL. In OHL, a novel state of EBV infection has been discovered with concurrent expression of replicative and transforming proteins, with all of these proteins contributing to the development of the lesion. Activation of signalling pathways and up-regulation of the viral receptor, proliferative and antiapoptotic genes by these proteins induce several of the histological features common to OHL, such as acanthosis and hyperproliferation. In contrast to other permissive herpesvirus infections, expression of EBV transforming proteins within the permissively infected OHL tissue enables epithelial cell survival and may enhance viral replication. Detection of KSHV in these HIV-infected individuals has been localized only to their saliva. Replicative and latent KSHV gene products have been detected in association with the development of oral KS lesions. EBV, but not human cytomegalovirus (HCMV), has been detected by PCR in minor salivary gland biopsies of HIV-associated salivary gland disease. Human papillomaviruses (HPV) are associated with oral warts in HIV-positive individuals; a diagnosis that appears to be increasing in frequency in the era of highly active antiretroviral therapy. To date, there appears to be little increase in the incidence of HPV-associated oral cancer. The mechanisms of interaction between HIV and HPV are not fully understood. Expression of viral gene products is clearly important and necessary for the development of multiple AIDS-associated oral lesions.
The prevalence of Epstein-Barr virus (EBV) and the recently discovered Kaposi's sarcoma associate... more The prevalence of Epstein-Barr virus (EBV) and the recently discovered Kaposi's sarcoma associated herpes virus, human herpesvirus 8 (KSHV or HHV8), was determined within oral lesions common to HIV infection including OHL, pseudoOHL (PHL), oral lymphoma, oral aphthous ulcers, and an oral Kaposi's sarcoma. METHODS: DNA and RNA were extracted from oral lesions. EBV and HHV8 genomes were detected by Southern blot and polymerase chain reaction (PCR), and viral expression was analyzed using PCR amplification of cDNA. RESULTS: Multiple EBV strains were detected within OHL with recombination across repeat sequences generating new viral variants. EBV expression in OHL included expression of some viral genes, usually expressed in latent .infections, that induce the EBV receptor. EBV replication was detected only within OHL lesions but not within adjacent Kaposi's tissue or oral aphthous ulcers while HHV8 was only detected within the Kaposi's lesions. CONCLUSIONS: These findings indicate that the OHL lesion is unique with viral replication and superinfection with additional EBV strains. Expression ofthe EBV receptor within the OHL lesion may promote superinfection which then activates EBV replication. The consistent detection of EBV replication only within OHL lesions and the detection of HHV8 only within Kaposi's sarcoma, strengthens the etiologic link between EBV and HHV8 infection to these specific pathologies.
Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the... more Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the cell type within the oropharynx capable of allowing EBV replication has never been conclusively identified. Using in situ cytohybridization, we demonstrated EBV DNA in oropharyngeal epithelial cells from 10 of 12 patients with infectious mononucleosis. In duplicates of specimens found to contain cell-associated EBV DNA, we detected EBV RNA in two of four samples, using a biotin-labeled EBV DNA probe, thereby confirming the intracellular location of the viral genome. In 20 of 28 throat washings analyzed, cytohybridization results and assays for cell-free infectious virus were in agreement. In seven of the eight remaining specimens, cytohybridization identified intracellular EBV DNA in the absence of detectable extracellular virus. We conclude that the oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis.
DISEASE clustering, the occurrence of cases that are close together in time and space, is often b... more DISEASE clustering, the occurrence of cases that are close together in time and space, is often believed to suggest an infectious cause.1 , 2 Despite numerous anecdotal reports of cancer clusters, Burkitt's lymphoma is the only human cancer for which there is clear-cut statistical evidence of time—space clustering.2 3 4 In general, reports of cancer clusters are uninformative, since most cancers have long, variable, or unknown latency periods between etiologic exposure and manifestation of the disease.2 , 4 , 5 A typical reported cluster is characterized by proximity in the time of diagnosis and in the residence of patients at diagnosis. However, the etiologic exposure may have occurred . . .
Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA delet... more Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA deleted for the EBV nuclear antigen 2 (EBNA2)-encoding gene that is essential for lymphocyte transformation. By polymerase chain reaction analysis, the deletion was found in virus from 5 of 33 healthy adult donors and 11 of 12 patients with concurrent human immunodeficiency virus infection. Lymphoblastoid cell lines that produce standard transforming EBV also harbored EBNA2-deleted virus in cells permissive of EBV replication. In vitro infectivity studies indicated that the DNA is packaged and transmissible, with biologic properties similar to those of a laboratory mutant, P3HR-1, which also lacks the EBNA2 gene. These findings, obtained from productively infected cell systems, provide evidence for the existence in nature of a transformation-incompetent EBV variant that may facilitate EBV persistence and the emergence of reactivation diseases.
Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes ... more Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes in vitro and has been detected in various types of EBV-associated malignancies. LMP-2A interferes with membrane signal transduction through phosphorylation of its hydrophilic N-terminal domain and binding of the cellular tyrosine kinases encoded by fyn and lyn. In vitro, the domain can block calcium influx and participate in signal transduction inducing cytokine production. These two activities are differently affected by site-directed mutagenesis of potentially phosphorylated amino acid residues. Several potential tyrosine protein kinase recognition motifs have been identified including an antigen recognition motif (ARAM). ARAMs are activated by tyrosine phosphorylation that enables binding of tyrosine protein kinases such as lyn and fyn. To assess the importance of potential sequence variation in natural EBV infection and in tumourigenesis, the sequence of the LMP-2A N-terminal domain was determined in 28 EBV isolates, including 14 fresh tumour isolates. Comparison of the corresponding sequences with the prototype B95 strain indicates that LMP-2 is generally conserved with a few base pair changes resulting in conservative amino acid changes in an occasional isolate. However, five single-base loci were frequently mutated, resulting in three patterns of sequence polymorphism in exon 1 of LMP-2A. The patterns did not segregate with EBV Type 1 or Type 2 and were detected in both lymphoid and epithelial tissues. Four of the most frequent mutations at loci 166627, 166750, 166796 and 166805 (codons 23, 63, 79 and 82) could potentially affect tyrosine protein kinase binding motifs. The pivotal tyrosines (codons 74 and 85) and leucines (codons 77 and 88) of the LMP-2 ARAM were not affected in any of the isolates, suggesting that ARAM function is important for EBV infection in vivo. However, the inter-spacing positions 79 and 82 were distinct in more than 50% of the isolates. These prevalent polymorphisms could influence interaction of the LMP-2 cytoplasmic domain with specific cellular ligand proteins.
Air pollution is a serious health problem in major cities in Mexico. The concentrations of monito... more Air pollution is a serious health problem in major cities in Mexico. The concentrations of monitored criteria pollutants have been above the US National Ambient Air Quality Standards for the last decade. To determine whether the number of primary malignant nasal and paranasal neoplasms has increased, we surveyed 256 such cases admitted to a major adult oncology hospital located in metropolitan Mexico City (MMC) for the period from 1976–1997 and to a tertiary hospital in Monterrey, an industrial city, for the period from 1993–1998. The clinical histories and histopathologic material were reviewed, and a brief clinical summary was written for each case. In the MMC hospital the number of newly diagnosed nasal and paranasal neoplasms per year for the period from 1976–1986 averaged 5.1, whereas for the next 11 years it increased to 12.5. The maximal increase was observed in 1995–1997, with an average of 20.3 new cases per year ( P = 0.0006). The predominant neoplasms in these series were...
Journal of the American Academy of Dermatology, 1989
To compare the therapeutic effects of surgical excision and orally administered acyclovir therapy... more To compare the therapeutic effects of surgical excision and orally administered acyclovir therapy on symptomatic oral hairy leukoplakia, 45 homosexual men who were seropositive for human immunodeficiency virus participated in a 3-month open-label study. In the 14 patients who had surgical excision, pain resolved in four symptomatic patients and the leukoplakia did not recur in the areas of excision. New foci of leukoplakia, however, appeared in 10 patients after 3 months. Of the 16 patients who received acyclovir therapy, 12 had a clinical regression, although recurrences were noted in all patients after 3 months. Three patients had resolution of pain while taking acyclovir; in two the pain recurred after acyclovir was discontinued. No spontaneous remissions of the leukoplakia occurred in the 15 patients who refused therapy. We conclude that surgical excision is effective in patients with symptomatic oral hairy leukoplakia.
Epstein-Barr virus (EBV) is associated with lymphomas and lymphoproliferative diseases that occur... more Epstein-Barr virus (EBV) is associated with lymphomas and lymphoproliferative diseases that occur mainly in immunocompromised patients, but the role EBV plays in their pathogenesis is unclear. The evidence linking EBV etiologically to these disorders includes the presence of EBV DNA and nuclear antigens in the lesions and serologic evidence that some patients with these lesions are experiencing primary or reactivated EBV infections. These syndromes may represent proliferation of cells latently infected with EBV, but the possibility of viral replication has not been rigorously studied. DNA extracted from biopsies of 35 lymphoproliferative diseases was probed with regions of the EBV genome capable of distinguishing circular, episomal DNA found in latency from linear, replicating EBV DNA. All samples contained restriction fragments characteristic of fused termini, indicative of circular, latent genomes. Thirteen samples contained additional restriction fragments diagnostic of linear EBV DNA. Therefore, replicating EBV DNA is found in approximately 40% of EBV-associated lymphoproliferative disorders.
By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enable... more By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enables Abs to acquire new effector functions that are crucial for the neutralization of invading pathogens. Class switching occurs through class switch DNA recombination (CSR) and usually requires engagement of CD40 on B cells by CD40 ligand on Ag-activated CD4+ T cells. CSR must be tightly regulated because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by EBV infection. In this study, we show that EBV induces CD40-independent CSR from Cμ to multiple downstream Cγ, Cα, and Cε genes through latent membrane protein 1 (LMP1), a CD40-like viral protein that signals in a ligand-independent fashion. LMP1-induced CSR is associated with transcriptional activation of germline Cγ, Cα, and Cε genes and triggers the up-regulation of activation-induced cytidine deaminase, a c...
A JB6 mouse epidermal recipient cell line has been used to detect nasopharyngeal carcinoma (NPC) ... more A JB6 mouse epidermal recipient cell line has been used to detect nasopharyngeal carcinoma (NPC) DNA-associated transforming activity that is not detectable in the NIH 3T3 focus assay. NPC DNA showed both transforming activity and activity for transferring sensitivity to tumor-promoterinduced neoplastic transformation, assayed in 2 different variants of mouse JB6 cells. Comparison of DNAs from various NPC sources that did or did not harbor EBV DNA and that varied in degree of differentiation showed similar transforming activities and similar activities for transferring promotion sensitivity. Thus both a NPC DNA-associated promotion sensitivity and an oncogenic activity function independently of concurrent EBV gene expression. 'To whom reprints should be addressed.
Acute mononucleosis rarely is associated with inflammatory arthritis. Although some patients with... more Acute mononucleosis rarely is associated with inflammatory arthritis. Although some patients with acute Epstein-Barr virus infection complain of arthralgia, only 4 patients with associated inflammatory synovitis have been reported (1,2). We report a patient with acute Epstein-Barr virus infection who had associated monoarticular inflammatory knee arthritis. Genomic analysis of Epstein-Barr virus from synovial fluid illustrated a reactive arthritis, rather than replication of Epstein-Barr virus.
This report describes the results of histopathologic and virologic studies in six patients with u... more This report describes the results of histopathologic and virologic studies in six patients with undifferentiated carcinoma (malignant lymphoepithelial lesions) of the salivary glands. Epstein-Barr virus (EBV) was detected in tumors from all six patients by DNA hybridization, while adjacent non-tumorous salivary gland tissue was negative for EBV in two patients tested for DNA and in three patients tested for Epstein-Barr nuclear antigen (EBNA). These findings add more evidence that these unusual salivary gland tumors are EBV-associated, and that EBV is specific to the tumor.
Recent studies have identified several EBV-specific transcripts in C15, an NPC passaged in nude m... more Recent studies have identified several EBV-specific transcripts in C15, an NPC passaged in nude mice1,2. These transcripts include both of the EBER RNAs, two related transcripts encoding LMP and several RNAs transcribed rightward from BamHI A3. Early replicative messages were not detected in C15, suggesting that this tumor is latently infected; therefore, the viral RNAs expressed from BamHI A are latent transcripts. The detection of transcription from BamHI A in latently infected epithelial cells is interesting because this region has not previously been identified as being transcriptionally active in latently infected lymphoid cells either by Northern blot or in situ hybridization4,5. This study investigates whether transcription from BamHI A is a consistent feature in NPC and attempts to determine whether these RNAs could possibly encode one or more viral antigens which are expressed in NPC.
A novel strain of Epstein-Barr virus (EBV) has been isolated from a young girl (SA) and her fathe... more A novel strain of Epstein-Barr virus (EBV) has been isolated from a young girl (SA) and her father both suffering from chronic active EBV infection (1). Selected throat washings from these patients induced the early antigen (EA) in Raji cells, observed using indirect immunofluorescence with polyvalent human antisera. Moreover, unlike virtually all natural EBV isolates, these throat washings never transformed cord blood leukocytes in a total of over 24 trials. Our previous experimental results also attest to the failure encountered in attempting to establish spontaneous lymphoblastoid cell lines (LCLs) from the peripheral blood of these patients. However, a spontaneous LCL was obtained from the mother of SA. Cell lines were only established by B95–8 induction and not without extreme difficulty. In fact, we were only able to obtain 3 B95–8-induced LCLs from the girl in approximately 30 trials, 2 of which were established in the presence of cyclosporin A.
Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aet... more Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aetiological agents of HIV-associated oral lesions. Oral lesions common to the early phase of the AIDS epidemic, including Kaposi's sarcoma (KS), oral aphthous ulceration, AIDS-associated oral lymphoma, and oral hairy leukoplakia (OHL), have been tested for the prevalence of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). While EBV DNA is detected by PCR in all of these lesions, abundant viral replication can only be detected in OHL. In OHL, a novel state of EBV infection has been discovered with concurrent expression of replicative and transforming proteins, with all of these proteins contributing to the development of the lesion. Activation of signalling pathways and up-regulation of the viral receptor, proliferative and antiapoptotic genes by these proteins induce several of the histological features common to OHL, such as acanthosis and hyperproliferation. In contrast to other permissive herpesvirus infections, expression of EBV transforming proteins within the permissively infected OHL tissue enables epithelial cell survival and may enhance viral replication. Detection of KSHV in these HIV-infected individuals has been localized only to their saliva. Replicative and latent KSHV gene products have been detected in association with the development of oral KS lesions. EBV, but not human cytomegalovirus (HCMV), has been detected by PCR in minor salivary gland biopsies of HIV-associated salivary gland disease. Human papillomaviruses (HPV) are associated with oral warts in HIV-positive individuals; a diagnosis that appears to be increasing in frequency in the era of highly active antiretroviral therapy. To date, there appears to be little increase in the incidence of HPV-associated oral cancer. The mechanisms of interaction between HIV and HPV are not fully understood. Expression of viral gene products is clearly important and necessary for the development of multiple AIDS-associated oral lesions.
The prevalence of Epstein-Barr virus (EBV) and the recently discovered Kaposi's sarcoma associate... more The prevalence of Epstein-Barr virus (EBV) and the recently discovered Kaposi's sarcoma associated herpes virus, human herpesvirus 8 (KSHV or HHV8), was determined within oral lesions common to HIV infection including OHL, pseudoOHL (PHL), oral lymphoma, oral aphthous ulcers, and an oral Kaposi's sarcoma. METHODS: DNA and RNA were extracted from oral lesions. EBV and HHV8 genomes were detected by Southern blot and polymerase chain reaction (PCR), and viral expression was analyzed using PCR amplification of cDNA. RESULTS: Multiple EBV strains were detected within OHL with recombination across repeat sequences generating new viral variants. EBV expression in OHL included expression of some viral genes, usually expressed in latent .infections, that induce the EBV receptor. EBV replication was detected only within OHL lesions but not within adjacent Kaposi's tissue or oral aphthous ulcers while HHV8 was only detected within the Kaposi's lesions. CONCLUSIONS: These findings indicate that the OHL lesion is unique with viral replication and superinfection with additional EBV strains. Expression ofthe EBV receptor within the OHL lesion may promote superinfection which then activates EBV replication. The consistent detection of EBV replication only within OHL lesions and the detection of HHV8 only within Kaposi's sarcoma, strengthens the etiologic link between EBV and HHV8 infection to these specific pathologies.
Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the... more Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the cell type within the oropharynx capable of allowing EBV replication has never been conclusively identified. Using in situ cytohybridization, we demonstrated EBV DNA in oropharyngeal epithelial cells from 10 of 12 patients with infectious mononucleosis. In duplicates of specimens found to contain cell-associated EBV DNA, we detected EBV RNA in two of four samples, using a biotin-labeled EBV DNA probe, thereby confirming the intracellular location of the viral genome. In 20 of 28 throat washings analyzed, cytohybridization results and assays for cell-free infectious virus were in agreement. In seven of the eight remaining specimens, cytohybridization identified intracellular EBV DNA in the absence of detectable extracellular virus. We conclude that the oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis.
DISEASE clustering, the occurrence of cases that are close together in time and space, is often b... more DISEASE clustering, the occurrence of cases that are close together in time and space, is often believed to suggest an infectious cause.1 , 2 Despite numerous anecdotal reports of cancer clusters, Burkitt's lymphoma is the only human cancer for which there is clear-cut statistical evidence of time—space clustering.2 3 4 In general, reports of cancer clusters are uninformative, since most cancers have long, variable, or unknown latency periods between etiologic exposure and manifestation of the disease.2 , 4 , 5 A typical reported cluster is characterized by proximity in the time of diagnosis and in the residence of patients at diagnosis. However, the etiologic exposure may have occurred . . .
Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA delet... more Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA deleted for the EBV nuclear antigen 2 (EBNA2)-encoding gene that is essential for lymphocyte transformation. By polymerase chain reaction analysis, the deletion was found in virus from 5 of 33 healthy adult donors and 11 of 12 patients with concurrent human immunodeficiency virus infection. Lymphoblastoid cell lines that produce standard transforming EBV also harbored EBNA2-deleted virus in cells permissive of EBV replication. In vitro infectivity studies indicated that the DNA is packaged and transmissible, with biologic properties similar to those of a laboratory mutant, P3HR-1, which also lacks the EBNA2 gene. These findings, obtained from productively infected cell systems, provide evidence for the existence in nature of a transformation-incompetent EBV variant that may facilitate EBV persistence and the emergence of reactivation diseases.
Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes ... more Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes in vitro and has been detected in various types of EBV-associated malignancies. LMP-2A interferes with membrane signal transduction through phosphorylation of its hydrophilic N-terminal domain and binding of the cellular tyrosine kinases encoded by fyn and lyn. In vitro, the domain can block calcium influx and participate in signal transduction inducing cytokine production. These two activities are differently affected by site-directed mutagenesis of potentially phosphorylated amino acid residues. Several potential tyrosine protein kinase recognition motifs have been identified including an antigen recognition motif (ARAM). ARAMs are activated by tyrosine phosphorylation that enables binding of tyrosine protein kinases such as lyn and fyn. To assess the importance of potential sequence variation in natural EBV infection and in tumourigenesis, the sequence of the LMP-2A N-terminal domain was determined in 28 EBV isolates, including 14 fresh tumour isolates. Comparison of the corresponding sequences with the prototype B95 strain indicates that LMP-2 is generally conserved with a few base pair changes resulting in conservative amino acid changes in an occasional isolate. However, five single-base loci were frequently mutated, resulting in three patterns of sequence polymorphism in exon 1 of LMP-2A. The patterns did not segregate with EBV Type 1 or Type 2 and were detected in both lymphoid and epithelial tissues. Four of the most frequent mutations at loci 166627, 166750, 166796 and 166805 (codons 23, 63, 79 and 82) could potentially affect tyrosine protein kinase binding motifs. The pivotal tyrosines (codons 74 and 85) and leucines (codons 77 and 88) of the LMP-2 ARAM were not affected in any of the isolates, suggesting that ARAM function is important for EBV infection in vivo. However, the inter-spacing positions 79 and 82 were distinct in more than 50% of the isolates. These prevalent polymorphisms could influence interaction of the LMP-2 cytoplasmic domain with specific cellular ligand proteins.
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Papers by N. Raab-traub