Mucocutaneous manifestations of HIV infection.

Indian J Dermatol Venereol Leprol. 2004 Mar-Apr;70(2):82-6

Authors: Shobhana A, Guha SK, Neogi DK

BACKGROUND AND AIMS: Human immunodeficiency virus (HIV) is associated with various mucocutaneous features, which may be the first pointer towards the existence of HIV infection. This study was done to note the different mucocutaneous lesions present in the HIV population in eastern India. METHODS: Four hundred and ten HIV seropositive patients attending the outpatient and inpatient departments were included in the study. RESULTS: Out of 410 HIV positives, 40% had mucocutaneous involvement at presentation. The mean age of the study population was 29 years and male to female ratio was 2.5:1. The common mucocutaneous morbidities included oral candidiasis (36%), dermatophytosis and gingivitis (13% each), herpes zoster (6%), herpes simplex and scabies (5% each). A striking feature, noted in 36% males, was straightening of hairs. Genital herpes was the commonest genital ulcer disease. Lesions associated with declining immunity included oral candidiasis, oral hairy leukoplakia and herpes zoster with median CD4 counts of 98, 62 and 198/ L respectively. CONCLUSION: Early recognition of mucocutaneous manifestations and associated STDs help in better management of HIV/AIDS.

PMID: 17642571 [PubMed]

Prevalence of oral hairy leukoplakia and epithelial infection by Epstein-Barr virus in pregnant women and diabetes mellitus patients--cytopathologic and molecular study.

Mem Inst Oswaldo Cruz. 2007 May;102(2):159-64

Authors: Milagres A, Dias EP, Tavares Ddos S, Cavalcante RM, Dantas VA, de Oliveira SP, Leite JP

Oral hairy leukoplakia (OHL) is generally reported in patients with severe immunosuppression, except for a few cases in individuals with moderate degree of immunodeficiency. It is a white lesion that appears mainly in the lateral border of the tongue, caused by Epstein-Barr virus (EBV). The nuclear changes caused by EBV (Cowdry A inclusion, ground glass and nuclear beading), observed in cytopathology, are specific and enough for the definitive diagnosis of OHL, independent of the identification of the virus. Here we investigated the prevalence of OHL and the presence of EBV-DNA in the lateral borders of the tongue from 90 pregnant women, 90 diabetes mellitus (DM) patients, 30 healthy individuals (negative group) and 30 HIV+ with OHL (positive group). Smears were analyzed by cytopathology and polymerase chain reaction (PCR). A case of subclinical OHL and candidiasis was identificated in a DM patient by cytopathologic analysis. PCR results demonstrated EBV-DNA in 65% of the pregnant women, in 35% of DM patients, and in 20% of the healthy individuals. We concluded that DM patients can develop OHL with a low prevalence. Furthermore, the prevalence of the EBV in lateral border of the tongue is larger in pregnant women than in healthy individuals.

PMID: 17426879 [PubMed - indexed for MEDLINE]

Epstein-Barr virus (EBV)-infected monocytes facilitate dissemination of EBV within the oral mucosal epithelium.

J Virol. 2007 Jun;81(11):5484-96

Authors: Tugizov S, Herrera R, Veluppillai P, Greenspan J, Greenspan D, Palefsky JM

Epstein-Barr virus (EBV) causes hairy leukoplakia (HL), a benign lesion of oral epithelium that occurs primarily in the setting of human immunodeficiency virus (HIV)-associated immunodeficiency. However, the mechanisms of EBV infection of oral epithelium are poorly understood. Analysis of HL tissues shows a small number of EBV-positive intraepithelial macrophages and dendritic/Langerhans cells. To investigate a role for these cells in spreading EBV to epithelial cells, we used tongue and buccal explants infected ex vivo with EBV. We showed that EBV first infects submucosal CD14(+) monocytes, which then migrate into the epithelium and spread virus to oral epithelial cells, initiating productive viral infection within the terminally differentiated spinosum and granulosum layers. Incubation of EBV-infected monocytes and oral explants with antibodies to CCR2 receptor and monocyte chemotactic protein 1 prevented entry of monocytes into the epithelium and inhibited EBV infection of keratinocytes. B lymphocytes played little part in the spread of EBV to keratinocytes in our explant model. However, cocultivation of EBV-infected B lymphocytes with uninfected monocytes in vitro showed that EBV may spread from B lymphocytes to monocytes. Circulating EBV-positive monocytes were detected in most HIV-infected individuals, consistent with a model in which EBV may be spread from B lymphocytes to monocytes, which then enter the epithelium and initiate productive viral infection of keratinocytes.

PMID: 17376918 [PubMed - indexed for MEDLINE]

Oral manifestations of HIV infection in children and adults receiving highly active anti-retroviral therapy [HAART] in Dar es Salaam, Tanzania.

BMC Oral Health. 2006;6:12

Authors: Hamza OJ, Matee MI, Simon EN, Kikwilu E, Moshi MJ, Mugusi F, Mikx FH, Verweij PE, van der Ven AJ

BACKGROUND: The aim of the study was to compare the prevalence and types of HIV-related oral lesions between children and adult Tanzanian patients on HAART with those not on HAART and to relate the occurrence of the lesions with anti-HIV drug regimen, clinical stage of HIV disease and CD4+ cell count. METHODS: Participants were 532 HIV infected patients, 51 children and 481 adults, 165 males and 367 females. Children were aged 2-17 years and adults 18 and 67 years. Participants were recruited consecutively at the Muhimbili National Hospital (MNH) HIV clinic from October 2004 to September 2005. Investigations included; interviews, physical examinations, HIV testing and enumeration of CD4+ T cells. RESULTS: A total of 237 HIV-associated oral lesions were observed in 210 (39.5%) patients. Oral candidiasis was the commonest (23.5%), followed by mucosal hyperpigmentation (4.7%). There was a significant difference in the occurrence of oral candidiasis (chi2 = 4.31; df = 1; p = 0.03) and parotid enlargement (chi2 = 36.5; df = 1; p = 0.04) between children and adults. Adult patients who were on HAART had a significantly lower risk of; oral lesions (OR = 0.32; 95% CI = 0.22-0.47; p = 0.005), oral candidiasis (OR = 0.28; 95% CI = 0.18-0.44; p = 0.003) and oral hairy leukoplakia (OR = 0.18; 95% CI = 0.04-0.85; p = 0.03). There was no significant reduction in occurrence of oral lesions in children on HAART (OR = 0.35; 95% CI = 0.11-1.14; p = 0.15). There was also a significant association between the presence of oral lesions and CD4+ cell count < 200 cell/mm3 (chi2 = 52.4; df = 2; p = 0.006) and with WHO clinical stage (chi2 = 121; df = 3; p = 0.008). Oral lesions were also associated with tobacco smoking (chi2 = 8.17; df = 2; p = 0.04). CONCLUSION: Adult patients receiving HAART had a significantly lower prevalence of oral lesions, particularly oral candidiasis and oral hairy leukoplakia. There was no significant change in occurrence of oral lesions in children receiving HAART. The occurrence of oral lesions, in both HAART and non-HAART patients, correlated with WHO clinical staging and CD4+ less than 200 cells/mm3.

PMID: 16916469 [PubMed]

Prevalence of oral hairy leukoplakia in 120 pediatric patients infected with HIV-1.

Braz Oral Res. 2006 Apr-Jun;20(2):103-7

Authors: Dias EP, Israel MS, Silva Junior A, Maciel VA, Gagliardi JP, Oliveira RH

Oral hairy leukoplakia (OHL) is an EBV (Epstein-Barr virus) opportunistic infection found in HIV-infected patients. It is an asymptomatic lesion that has an important prognostic value in AIDS. Differently from what takes place with HIV adult patients, OHL has been described in the literature as having a very small prevalence in pediatric patients. Therefore, the aim of this study was to investigate the prevalence of OHL in HIV pediatric patients using cytopathology. The sample consisted of 120 patients who were submitted to oral examination and had material scraped from both sides of their tongues. The diagnostic criterion was based on the identification of nuclear alterations. Clinical OHL was identified in two (1.67%) patients. The cytopathology revealed twenty (16.7%) cases of subclinical OHL. Our results show that in pediatric patients the prevalence of OHL may be larger than that described in the literature.

PMID: 16878201 [PubMed - indexed for MEDLINE]

(A3) HIV Phenotypes, oral lesions, and management of HIV-related disease.

Adv Dent Res. 2006;19(1):122-9

Authors: Blignaut E, Patton LL, Nittayananta W, Ramirez-Amador V, Ranganathan K, Chattopadhyay A

Workshop participants discussed: the role of HIV subtypes in disease; the treatment of oral candidiasis; the relationship between and among viral load, CD4+ counts, oral candidiasis and oral hairy leukoplakia, pigmentation; and the development of a reliable oral index to predict disease progression. Regarding HIV, the literature revealed that Type I (HIV-I), in particular group M, is involved in the majority (90%) of documented infections, and groups N and O to a lesser extent. Viral envelope diversity led to the subclassification of the virus into nine subtypes, or clades-A-D, F-H, J, and K-each dominating in different geographical areas. HIV-2, currently occurring mostly in West Africa, appears to be less virulent. No evidence could be produced of any direct impact of type, subtype, or clade on oral lesions, and participants believed that further research is not feasible. Oral candidiasis in patients from resource-poor countries should be prevented. When the condition does occur, it should be treated until all clinical symptoms disappear. Oral rinsing with an antimicrobial agent was suggested to prevent recurrence of the condition, to reduce cost, and to prevent the development of antifungal resistance. Lawsone methyl ether, isolated from a plant (Rhinacanthus nasutus leaves) in Thailand, is a cost-effective mouthrinse with potent antifungal activity. Evidence from a carefully designed prospective longitudinal study on a Mexican cohort of HIV/AIDS patients, not receiving anti-retroviral treatment, revealed that the onset of oral candidiasis and oral hairy leukoplakia was heralded by a sustained reduction of CD4+, with an associated sharp increase in viral load. Analysis of the data obtained from a large cohort of HIV/AIDS patients in India could not establish a systemic or local cause of oral melanin pigmentation. A possible explanation was a dysfunctional immune system that increased melanin production. However, longitudinal studies may contribute to a better understanding of this phenomenon. Finally, a development plan was presented that could provide a reliable prediction of disease progression. To be useful in developing countries, the index should be independent of costly blood counts and viral load.

PMID: 16672562 [PubMed - indexed for MEDLINE]

Oral lesions in HIV infection in developing countries: an overview.

Adv Dent Res. 2006;19(1):63-8

Authors: Ranganathan K, Hemalatha R

HIV infection is a major global health problem affecting developing and developed countries alike. Oral lesions that are associated with this disease are important, since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. Oral lesions in HIV infection have been well-documented in developed countries, but there are fewer reports on oral lesions from developing countries. Oral candidiasis is the most common opportunistic infection seen in all continents. Kaposi's sarcoma has been reported only from Africa and Latin America, while histoplasmosis and penicilliosis were reported in patients with advanced disease from Thailand. HIV-associated salivary gland disease has a high prevalence in Africa and Latin America, especially in the pediatric group. It is clear that there are considerable regional variations in the oral manifestations of HIV infection, depending both on the populations studied and on the clinical expertise available, among other factors. Well-designed and -documented studies are necessary for the correct assessment of the nature and magnitude of the problem in developing countries, if oral health measures are to be effectively formulated for the HIV-infected.

PMID: 16672552 [PubMed - indexed for MEDLINE]

[Oral manifestations in HIV infection]

Tidsskr Nor Laegeforen. 2006 Apr 27;126(9):1218-21

Authors: Steinsvoll S, Herlofson BB

In this review article, oral lesions in relation to HIV infection are presented and discussed. Lesions such as oral candidiasis, hairy leukoplakia and necrotising gingivitis or periodontitis may be the first sign of an HIV infection or of its progression. Almost all HIV-infected patients will contract oral diseases. Dentists and physicians play an essential role in early recognition of signs and symptoms of HIV disease or of its progression. Only through such recognition can appropriate definitive diagnostic testing be conducted and appropriate therapeutic intervention for the condition be considered. It is pivotal that both dentists and physicians are familiar with the most frequently occurring oral symptoms of HIV infection.

PMID: 16670745 [PubMed - indexed for MEDLINE]

Epstein-Barr virus in oral hairy leukoplakia scrapes: identification by PCR.

Braz Oral Res. 2005 Oct-Dec;19(4):317-21

Authors: Komatsu TL, Rivero ER, Gallottini de Magalh&#xE3;es MH, Nunes FD

Oral hairy leukoplakia (OHL) is a lesion associated with a compromised immune system, and its diagnosis is determined by the demonstration of the presence of Epstein-Barr virus (EBV) in lesional tissue. The purpose of this article was to develop a simple technique to help the diagnosis of OHL, using PCR as an alternative technique to evidence EBV in scrapings. DNA samples were obtained by scraping the lateral border of the tongue of 38 adult patients: 29 HIV-positive patients (4 with clinical evidence of OHL; 4 with history of OHL, but without lesion at the moment the samples were collected; and 21 without clinical evidence of OHL), and 9 healthy volunteers for the control group. DNA was extracted from scrapes and amplified by PCR using specific primers for EBV. Of the 29 cases of HIV-positive patients, 22 (75.86%) were positive for EBV: 2 patients with clinical evidence of OHL, 4 patients with history of OHL, but without lesion at the moment the samples were collected, and 16 patients without clinical evidence of OHL. In the control group, samples of 5 (55.56%) healthy volunteers presented amplification for EBV. We concluded that the use of PCR in oral scrapes suggests a high sensitivity but low specificity for the diagnosis of OHL.

PMID: 16491263 [PubMed - indexed for MEDLINE]

Prevalence of oral lesions in HIV patients related to CD4 cell count and viral load in a Venezuelan population.

Med Oral Patol Oral Cir Bucal. 2006 Jan;11(1):E33-9

Authors: Bravo IM, Correnti M, Escalona L, Perrone M, Brito A, Tovar V, Rivera H

AIM: To determine the prevalence of oral lesions in a HIV+ group of patients, related to CD4 cell count and viral load in a Venezuelan population. MATERIALS AND METHODS: In the present study, we evaluated 75 HIV+ adult patients, attended at the Center of Infectious Diseases, at the Faculty of Dentistry, Central University of Venezuela. Each patient was clinically examined for detection of oral mucosal lesions. In addition, CD4 cell count was determined by flow cytometry, as well as viral load by RT-PCR (Amplicor HIV-RNA, TM test 1.5, Roche). RESULTS: 85% (64/75) of HIV/AIDS patients showed associated HIV lesions. Oral Candidiasis constituted the most common lesion representing a 61% (39/64), followed by Oral Hairy Leukoplakia 53% (34/64); Oral Leukoplakia 34% (22/64), Melanic Hyperpigmentation 38% (18/64); Papilloma 13 (6/64), Lineal Gingival Erythema 8% (5/64); Aphtous Recurrent Stomatitis 5% (4/64) and Kaposi's Sarcoma 5% (3/64). Only one case of the following lesions were represented by Non Hodgkin Lymphoma, Multifocal Epithelial Hyperplasia, Recurrent Herpes, Histoplasmosis and Molluscum Contagiosum. The patients with a viral load of 30.000 copies/mm3 exhibited oral lesions related with HIV, independent of CD4 cell count, although patients with CD4+ levels of 200 cel/mm3 were more susceptible to develop these lesions. CONCLUSIONS: The most common oral lesion was Oral Candidiasis followed by Oral Hairy Leukoplakia, Oral Leukoplakia and Melanic Hyperpigmentation. A high viral load was strongly associated to the oral lesions occurrence independently of CD4+ cell count.

PMID: 16388291 [PubMed - indexed for MEDLINE]

Oral manifestations of HIV disease.

Top HIV Med. 2005 Dec-2006 Jan;13(5):143-8

Authors: Reznik DA

HIV-related oral conditions occur in a large proportion of patients, and frequently are misdiagnosed or inadequately treated. Dental expertise is necessary for appropriate management of oral manifestations of HIV infection or AIDS, but many patients do not receive adequate dental care. Common or notable HIV-related oral conditions include xerostomia, candidiasis, oral hairy leukoplakia, periodontal diseases such as linear gingival erythema and necrotizing ulcerative periodontitis, Kaposi's sarcoma, human papilloma virus-associated warts, and ulcerative conditions including herpes simplex virus lesions, recurrent aphthous ulcers, and neutropenic ulcers.

PMID: 16377852 [PubMed - indexed for MEDLINE]

Oral lesions in infection with human immunodeficiency virus.

Bull World Health Organ. 2005 Sep;83(9):700-6

Authors: Coogan MM, Greenspan J, Challacombe SJ

This paper discusses the importance of oral lesions as indicators of infection with human immunodeficiency virus (HIV) and as predictors of progression of HIV disease to acquired immunodeficiency syndrome (AIDS). Oral manifestations are among the earliest and most important indicators of infection with HIV. Seven cardinal lesions, oral candidiasis, hairy leukoplakia, Kaposi sarcoma, linear gingival erythema, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis and non-Hodgkin lymphoma, which are strongly associated with HIV infection, have been identified and internationally calibrated, and are seen in both developed and developing countries. They may provide a strong indication of HIV infection and be present in the majority of HIV-infected people. Antiretroviral therapy may affect the prevalence of HIV-related lesions. The presence of oral lesions can have a significant impact on health-related quality of life. Oral health is strongly associated with physical and mental health and there are significant increases in oral health needs in people with HIV infection, especially in children, and in adults particularly in relation to periodontal diseases. International collaboration is needed to ensure that oral aspects of HIV disease are taken into account in medical programmes and to integrate oral health care with the general care of the patient. It is important that all health care workers receive education and training on the relevance of oral health needs and the use of oral lesions as surrogate markers in HIV infection.

PMID: 16211162 [PubMed - indexed for MEDLINE]

Interferon regulatory factor 7 is negatively regulated by the Epstein-Barr virus immediate-early gene, BZLF-1.

J Virol. 2005 Aug;79(15):10040-52

Authors: Hahn AM, Huye LE, Ning S, Webster-Cyriaque J, Pagano JS

Virus infection stimulates potent antiviral responses; specifically, Epstein-Barr virus (EBV) infection induces and activates interferon regulatory factor 7 (IRF-7), which is essential for production of alpha/beta interferons (IFN-alpha/beta) and upregulates expression of Tap-2. Here we present evidence that during cytolytic viral replication the immediate-early EBV protein BZLF-1 counteracts effects of IRF-7 that are central to host antiviral responses. We initiated these studies by examining IRF-7 protein expression in vivo in lesions of hairy leukoplakia (HLP) in which there is abundant EBV replication but the expected inflammatory infiltrate is absent. This absence might predict that factors involved in the antiviral response are absent or inactive. First, we detected significant levels of IRF-7 in the nucleus, as well as in the cytoplasm, of cells in HLP lesions. IRF-7 activity in cell lines during cytolytic viral replication was examined by assay of the IRF-7-responsive promoters, IFN-alpha4, IFN-beta, and Tap-2, as well as of an IFN-stimulated response element (ISRE)-containing reporter construct. These reporter constructs showed consistent reduction of activity during lytic replication. Both endogenous and transiently expressed IRF-7 and EBV BZLF-1 proteins physically associate in cell culture, although BZLF-1 had no effect on the nuclear localization of IRF-7. However, IRF-7-dependent activity of the IFN-alpha4, IFN-beta, and Tap-2 promoters, as well as an ISRE promoter construct, was inhibited by BZLF-1. This inhibition occurred in the absence of other EBV proteins and was independent of IFN signaling. Expression of BZLF-1 also inhibited activation of IRF-7 by double-stranded RNA, as well as the activity of a constitutively active mutant form of IRF-7. Negative regulation of IRF-7 by BZLF-1 required the activation domain but not the DNA-binding domain of BZLF-1. Thus, EBV may subvert cellular antiviral responses and immune detection by blocking the activation of IFN-alpha4, IFN-beta, and Tap-2 by IRF-7 through the medium of BZLF-1 as a negative regulator.

PMID: 16014964 [PubMed - indexed for MEDLINE]

Oral lesions in a group of kidney transplant patients.

Med Oral Patol Oral Cir Bucal. 2005 May-Jul;10(3):196-204

Authors: de la Rosa-Garc&#xED;a E, Mondragón-Padilla A, Irigoyen-Camacho ME, Bustamante-Ramírez MA

AIM: To assess the prevalence of oral mucosa lesions (OL) in a group of kidney transplant (KT) patients, and analyze possible OL associations with one another and with drugs use and relevant clinical and laboratory variables. METHODOLOGY: Transversal study, in which consecutive KT patients from the nephrology outpatient service at a General Zonal Hospital were examined. The prevalence of several types of OL was assessed, and their possible statistical associations with one another and total leukocyte count, renal function, the simplified oral hygiene index (S-OHI), cyclosporin-A (CsA) dose and blood levels, and nifedipine use was analyzed. A logistic regression model was used to analyze the association between gingival hyperplasia (GH) and CsA dose and nifedipine use. RESULTS: Fifty (55.6%) men and forty (44.4%) women were studied. Sixty percent of the patients had at least one OL. Oral candidiasis (OC) was found in 18.7%; 13% had lesions clinically compatible with hairy leukoplakia (CHL). An association was found between OC and CHL (P<0.05). Saburral tongue (ST) was found in 22% of the patients and gingival hyperplasia (GH) in 49%, which was distributed as follows: Grade 1 in 11 (12.2%); Grade 2 in 26 (28.9%), and Grade 3 in 7 (7.8%). Logistic regression results showed an association between GH and poor oral hygiene (P< 0.001), but not to either CsA dose or blood levels, or nifedipine use (P=0.075). CONCLUSION: Sixty percent of the KT patients had at least one OL. The association between GH and poor oral hygiene corroborate the need for oral hygiene practices supervision in the transplant patient.

PMID: 15876960 [PubMed - indexed for MEDLINE]

Whitish papules and plaques on the tongue.

Am Fam Physician. 2004 Dec 15;70(12):2353-4

Authors: Khachemoune A, Ogholikhan M

PMID: 15617301 [PubMed - indexed for MEDLINE]

Epstein-Barr virus infection in ex vivo tonsil epithelial cell cultures of asymptomatic carriers.

J Virol. 2004 Nov;78(22):12613-24

Authors: Pegtel DM, Middeldorp J, Thorley-Lawson DA

Epstein-Barr virus (EBV) is found frequently in certain epithelial pathologies, such as nasopharyngeal carcinoma and oral hairy leukoplakia, indicating that the virus can infect epithelial cells in vivo. Recent studies of cell lines imply that epithelial cells may also play a role in persistent EBV infection in vivo. In this report, we show the establishment and characterization of an ex vivo culture model of tonsil epithelial cells, a likely site for EBV infection in vivo. Primary epithelial-cell cultures, generated from tonsil explants, contained a heterogeneous mixture of cells with an ongoing process of differentiation. Keratin expression profiles were consistent with the presence of cells from both surface and crypt epithelia. A small subset of cells could be latently infected by coculture with EBV-releasing cell lines, but not with cell-free virus. We also detected viral-DNA, -mRNA, and -protein expression in cultures from EBV-positive tonsil donors prior to in vitro infection. We conclude that these cells were either already infected at the time of explantation or soon after through cell-to-cell contact with B cells replicating EBV in the explant. Taken together, these findings suggest that the tonsil epithelium of asymptomatic virus carriers is able to sustain EBV infection in vivo. This provides an explanation for the presence of EBV in naso- and oropharyngeal pathologies and is consistent with epithelial cells playing a role in the egress of EBV during persistent infection.

PMID: 15507648 [PubMed - indexed for MEDLINE]

The C-mer gene is induced by Epstein-Barr virus immediate-early protein BRLF1.

J Virol. 2004 Nov;78(21):11778-85

Authors: Li Y, Mahajan NP, Webster-Cyriaque J, Bhende P, Hong GK, Earp HS, Kenney S

BRLF1 (R) is one of two Epstein-Barr virus (EBV) immediate-early proteins that mediate the switch from the latent to the lytic form of viral replication. In this report, we show that R induces expression of the cellular C-mer gene in a variety of cell lines. C-mer expression was detected in lymphoblastoid cells immortalized with wild-type EBV but not in lymphoblastoid cells immortalized with an EBV that had BRLF1 deleted. Oral hairy leukoplakia tongue tissue, which contains the lytic form of EBV replication, also has enhanced C-mer expression. C-mer is a receptor tyrosine kinase activated by the ligand Gas6. C-mer is required for phagocytosis of apoptotic debris by monocytes/macrophages and retinal pigment epithelial cells and is capable of producing an antiapoptotic signal. Modulation of the C-mer signal transduction cascade by a variety of different approaches did not alter the ability of R to induce lytic EBV gene transcription. Therefore, C-mer activation may be important for some other aspect of lytic EBV infection.

PMID: 15479819 [PubMed - indexed for MEDLINE]

Oral lesions and conditions associated with human immunodeficiency virus infection in 1000 South Indian patients.

Ann Acad Med Singapore. 2004 Jul;33(4 Suppl):37-42

Authors: Ranganathan K, Umadevi M, Saraswathi TR, Kumarasamy N, Solomon S, Johnson N

INTRODUCTION: Human immunodeficiency virus (HIV) infection is a major health problem in India. The importance of oral lesions as clinical features of HIV infection and their gender specificity have been reported worldwide. However, there are very few reports on this aspect from the Indian subcontinent. MATERIALS AND METHODS: The study population comprised 1000 consecutive HIV seropositive patients presenting to YRG CARE, a non-governmental organisation in Chennai, South India. The oral lesions were diagnosed based on clinical appearance using international criteria. Data were entered into a database and analysed using the SPSS package. RESULTS: The male-to-female ratio was 3.4:1, and 95% of the patients had acquired infection via heterosexual contact. Majority of the patients (84%) were in the 21- to 40-year-old age groups. Pulmonary tuberculosis (12%) was the most common systemic finding. Oral lesions were seen in 86.6% of the patients. Gingivitis (72.3%) and periodontitis (33.2%) were the most common lesions followed by oral pigmentation (26.3%), oral candidiasis (23.8%), angular cheilitis (7.9%), oral ulcers (3.3%), oral hairy leukoplakia (2.1%), oral submucous fibrosis (0.9%) and leukoplakia (1.5%). The prevalence of oral candidiasis, periodontitis and oral hairy leukoplakia was higher in males than in females. CONCLUSIONS: Oral lesions occur commonly in HIV infection. A comprehensive oral examination plays an important role not only in the management of the patients, but also in assessing the immune status and in their follow-up.

PMID: 15389305 [PubMed - indexed for MEDLINE]

Cutaneous manifestations of human immunodeficiency virus infection in Taiwan.

Kaohsiung J Med Sci. 2004 May;20(5):216-24

Authors: Tzung TY, Yang CY, Chao SC, Lee JY

Cutaneous manifestations are common and often the presenting feature of human immunodeficiency virus (HIV) infection, but a comprehensive study of HIV-associated skin lesions is not available in Taiwan. We reviewed all skin lesions in all HIV patients diagnosed in our department between 1990 and 1998 to document the spectrum of skin manifestations, the frequency of each disorder, and their relationship with CD4 counts. A total of 64 HIV patients were studied, including 38 with acquired immunodeficiency syndrome (AIDS) (CD4 < 200 x 10(6) cells/L) and 26 who had not developed AIDS (non-AIDS). There were 142 episodes of skin conditions representing 25 different skin diseases, including oral candidiasis (15% in non-AIDS vs 71% in AIDS patients), drug eruptions, herpes simplex, seborrheic dermatitis, dermatophytosis, herpes zoster, secondary syphilis, condyloma acuminatum, Kaposi's sarcoma (16% among AIDS patients), hairy leukoplakia, and molluscum contagiosum (13% among AIDS patients), in decreasing order. Several unusual cases are briefly described, including verrucous herpes infection, condyloma-like molluscum contagiosum, and AIDS-associated pigmented erythroderma. In our study, 70% of all HIV patients had skin diseases, with an average of 2.2 conditions per patient (3.2 in AIDS patients vs 0.7 in non-AIDS patients; p < 0.001). A broad spectrum of HIV-associated skin diseases was observed in our series. The frequency of HIV-associated skin disease was 92% in AIDS patients and 39% in non-AIDS patients; 78% of skin lesions in AIDS patients were diagnosed when CD4 counts were below 100 x 10(6) cells/L.

PMID: 15233232 [PubMed - indexed for MEDLINE]

[Clinical manifestation of AIDS in oral and maxillofacial region (Report of a case)]

Shanghai Kou Qiang Yi Xue. 1998 Jun;7(2):85-7

Authors: Wang SC, Xu S, Wu X

The prevalence morbidity of AIDS rises day after day. As the first symptom of this disease usually occurs in maxillofacial region,it must be well attentioned to the dentists. Here introducing a case who was a patient of AIDS. He was first see doctor in july 1995 in our Department, associating with foreign documents, the authors described all kinds of clinic symptoms of AIDS on oral and maxillofacial region in early to late stage.The typical one includes hairy leukoplakia,monilia albicans infection of angular stomatitis and mucous membrane,KS,etc.At last,the authors indicated there are some preventive methods to the disease for the dentists.

PMID: 15071674 [PubMed - as supplied by publisher]

Fatty acid synthase expression is induced by the Epstein-Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression.

J Virol. 2004 Apr;78(8):4197-206

Authors: Li Y, Webster-Cyriaque J, Tomlinson CC, Yohe M, Kenney S

The Epstein-Barr virus (EBV) immediate-early (IE) protein BRLF1 (R) is a transcription factor that induces the lytic form of EBV infection. R activates certain early viral promoters through a direct binding mechanism but induces transcription of the other EBV IE gene, BZLF1 (Z), indirectly through cellular factors binding to a CRE motif in the Z promoter (Zp). Here we demonstrate that R activates expression of the fatty acid synthase (FAS) cellular gene through a p38 stress mitogen-activated protein kinase-dependent mechanism. B-cell receptor engagement of Akata cells also increases FAS expression. The FAS gene product is required for de novo synthesis of the palmitate fatty acid, and high-level FAS expression is normally limited to liver, brain, lung, and adipose tissue. We show that human epithelial tongue cells lytically infected with EBV (from oral hairy leukoplakia lesions) express much more FAS than uninfected cells. Two specific FAS inhibitors, cerulenin and C75, prevent R activation of IE (Z) and early (BMRF1) lytic EBV proteins in Jijoye cells. In addition, cerulenin and C75 dramatically attenuate IE and early lytic gene expression after B-cell receptor engagement in Akata cells and constitutive lytic viral gene expression in EBV-positive AGS cells. However, FAS inhibitors do not reduce lytic viral gene expression induced by a vector in which the Z gene product is driven by a strong heterologous promoter. In addition, FAS inhibitors do not reduce R activation of a naked DNA reporter gene construct driven by the Z promoter (Zp). These results suggest that cellular FAS activity is important for induction of Z transcription from the intact latent EBV genome, perhaps reflecting the involvement of lipid-derived signaling pathways or palmitoylated proteins. Furthermore, using FAS inhibitors may be a completely novel approach for blocking the lytic form of EBV replication.

PMID: 15047835 [PubMed - indexed for MEDLINE]

Molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in immunosuppressed rhesus macaques.

J Virol. 2004 Apr;78(7):3455-61

Authors: Kutok JL, Klumpp S, Simon M, MacKey JJ, Nguyen V, Middeldorp JM, Aster JC, Wang F

Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with epithelial cell and B-cell malignancies. EBV infection of B lymphocytes is essential for acute and persistent EBV infection in humans; however, the role of epithelial cell infection in the normal EBV life cycle remains controversial. The rhesus lymphocryptovirus (LCV) is an EBV-related herpesvirus that naturally infects rhesus macaques and can be used experimentally to model persistent B-cell infection and B-cell lymphomagenesis. We now show that the rhesus LCV can infect epithelial cells in immunosuppressed rhesus macaques and can induce epithelial cell lesions resembling oral hairy leukoplakia in AIDS patients. Electron microscopy, immunohistochemistry, and DNA-RNA in situ hybridization were used to identify the presence of a lytic rhesus LCV infection in these proliferative, hyperkeratotic, or parakeratotic epithelial cell lesions. These studies demonstrate that the rhesus LCV has tropism for epithelial cells, in addition to B cells, and is a relevant animal model system for studying the role of epithelial cell infection in EBV pathogenesis.

PMID: 15016868 [PubMed - indexed for MEDLINE]

[Clinical and research advances in oral AIDS]

Shanghai Kou Qiang Yi Xue. 2001 Sep;10(3):193-5

Authors: Chou L

HIV infection continues to spread throughout the world without any end insight, and is still the fastest increasing cause of mortality. The majority of HIV-infected patients have HIV-associated oral mucosal lesions at different stages of the disease. In many patients, oral lesions could be the first sign of their HIV infection. Therefore, knowledge of HIV infection has become a critically important requirement for professionals responsible for oral health care delivery and early detection of HIV infection. Oral candidiasis (OC), hairy leukoplakia (HL), and Kaposi sarcoma (KS) are the most common oral lesions strongly associated with HIV infection.Both pseudomembranous and erythematous OC occur in over 95% of HIV-infected patients throughout the oral cavity, highly related to a reversed CD4/CD8 cell ratio.Attached gingiva would be a unique site of OC, only occurring in HIV-infected patients. Because of decreased gastric acid secretion in most HIV-infected patients, fluconazole, the antifungal drug that can be absorbed easily despite the gastric pH change, would be the best choice for systemic antifungal treatment. HL primarily occurs in HIV-infected male patients on the lateral border of the tongue. However, similar-appearing changes can also occur in HIV-negative persons. HL is not related to precancerous leukoplakia or dysplasia. Our latest study indicated that the infection of Epstein-Barr virus (EBV) might not be the definitive criteria for the diagnosis of HL and that the reciprocal activation of EBV and HIV within the epithelium may be the critical event in the development of HL. Our study demonstrated that CD4-bearing oral mucosal Langerhans cells (LC) could be the target of HIV infection, the effector to alter LC number and its antigen processing capability, as well as the vector to pass the virus to submucosal memory T cells, which would be responsible for the second pathway of HIV transmission through mucosal contact with HIV. HIV-associated depletion of LC would lead to impairment of the oral mucosal surveillant system, resulting in opportunistic oral mucosal lesions, such as OC and HL. KS has been the most common tumor associated with HIV infection and has been one of the AIDS defining diseases. The latest study indicated that this tumor is related to opportunistic infection of human herpes simplex virus 8. Because of its reactive type nature clinically and histologically, KS has now been considered a pseudomalignancy. Intralesional injection of cytotoxic drugs has been effective in treatment.Since HIV-infected patients have demonstrated a higher propensity for developing allergic and adverse reactions to antibiotics, bleeding tendency and slow wound healing after dental surgery, decreased levels of neutrophil counts, and xerostomia, a modified dental therapy would be essential for management of HIV-infected dental patients. In addition, concerns about HIV transmission from patient to dentist, dentist to patient, and between patients should be clarified.

PMID: 14993986 [PubMed]

Incidence of oral lesions in HIV-1-infected women: reduction with HAART.

J Dent Res. 2004 Feb;83(2):145-50

Authors: Greenspan D, Gange SJ, Phelan JA, Navazesh M, Alves ME, MacPhail LA, Mulligan R, Greenspan JS

Few studies assess the effectiveness of HAART on reducing the incidence and recurrence of oral lesions. We investigated such changes among 503 HIV+ women over six years in the Women's Interagency HIV Study. The incidence of erythematous candidiasis (EC), pseudomembranous candidiasis (PC), hairy leukoplakia (HL), and warts was computed over follow-up visits after HAART initiation compared with before HAART initiation. Analysis of our data demonstrates a strong decrease in candidiasis after HAART initiation. The incidence of EC fell to 2.99% from 5.48% (RR 0.545); PC fell to 2.85% from 6.70% (RR 0.425); and EC or PC fell to 3.43% from 7.35% (RR 0.466). No changes were seen in HL or warts. Higher HIV-RNA was associated with greater incidence of candidiasis and HL, but not warts. Analysis of these data indicates that recurrence and incidence of candidiasis are reduced by HAART, and that recurrence is reduced independently of CD4 and HIV-RNA.

PMID: 14742653 [PubMed - indexed for MEDLINE]

Epstein-Barr virus replication in tongue epithelial cells.

J Gen Virol. 2002 Dec;83(Pt 12):2995-8

Authors: Herrmann K, Frangou P, Middeldorp J, Niedobitek G

Epstein-Barr virus (EBV) persistently infects B-cells in humans and can be shed into the saliva. The cellular source of infectious virus is uncertain. Hairy leukoplakia, an AIDS-associated lesion of the tongue, supports EBV replication in epithelial cells. However, the general significance of this observation has remained doubtful. Using immunohistochemistry and in situ hybridization, we demonstrate evidence of EBV replication in tongue epithelial cells in 4 of 168 samples from 84 autopsy cases. Thus, in patients who do not have AIDS, squamous epithelial cells of the tongue rarely support EBV replication. However, all individuals with evidence of EBV replication were either on immunosuppressive therapy or were terminally ill cancer patients, suggesting that an impairment of the immune system may have allowed EBV replication to occur at this site. Thus, our findings are consistent with the idea that EBV replication in oropharyngeal epithelial cells is an infrequent event.

PMID: 12466475 [PubMed - indexed for MEDLINE]

Identification of Epstein-Barr virus strain variants in hairy leukoplakia and peripheral blood by use of a heteroduplex tracking assay.

J Virol. 2002 Oct;76(19):9645-56

Authors: Sitki-Green D, Edwards RH, Webster-Cyriaque J, Raab-Traub N

Epstein-Barr virus (EBV) strains can be distinguished by specific sequence variations in the LMP1 gene. In this study, a heteroduplex tracking assay (HTA) specific for LMP1 was developed to precisely identify the prototypic undeleted strain B958, other undeleted strains (Ch2, AL, NC, and Med-), and strains with the 30-bp deletion (Med+ and Ch1). This technique also provides an estimate of the relative abundance of strains in patient samples. In this study, EBV strains were identified in 25 hairy leukoplakia (HLP) biopsies and six matched peripheral blood samples and throat washes with the LMP1-HTA. To investigate the relationship of the virus found in the peripheral blood to that in the HLP lesion, the strain variants in the peripheral blood B lymphocytes and those present within the epithelial cells in the HLP lesion and in throat washes were identified. In many of the subjects, compartmental differences in the EBV strain profiles in the oral cavity and peripheral blood were readily apparent. The throat wash specimens usually had a strain profile similar to that within the corresponding HLP sample, which was distinct from the strain profile detected in the peripheral blood. These analyses reveal that the nature of EBV infection can be very dynamic, with changes in relative strain abundance over time as well as the appearance of new strains. The patterns of abundance in the blood and oral cavity provide evidence for compartmentalization and for the transmission of strains between the blood and oropharynx.

PMID: 12208943 [PubMed - indexed for MEDLINE]

A defective, rearranged Epstein-Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease.

Am J Pathol. 2002 Mar;160(3):781-6

Authors: Gan YJ, Razzouk BI, Su T, Sixbey JW

A ubiquitous herpesvirus that establishes life-long infection, the Epstein-Barr virus (EBV) has yielded little insight into how a single agent in general accord with its host can produce diverse pathologies ranging from oral hairy leukoplakia to nasopharyngeal carcinoma, from infectious mononucleosis to Hodgkin's disease (HD) and Burkitt's lymphoma. Its pathogenesis is further confounded by the less than total association of virus with histologically similar tumors. In other viral systems, defective (interfering) viral genomes are known to modulate outcome of infection, with either ameliorating or intensifying effects on disease processes initiated by prototype strains. To ascertain whether defective EBV genomes are present in HD, we examined paraffin-embedded tissue from 56 HD cases whose EBV status was first determined by cytohybridization for nonpolyadenylated EBV RNAs (EBERs). Using both standard polymerase chain reaction (PCR) and PCR in situ hybridization, we successfully amplified sequences that span abnormally juxtaposed BamHI W and Z fragments characteristic of defective heterogeneous (het) EBV DNA from 10 of 32 (31%) EBER-positive tumors. Of 24 EBER-negative HD, 8 yielded PCR products indicating presence of het EBV DNA. Two of these contained defective EBV in the apparent absence of the prototype virus. Of the 42 tumors analyzed for defective EBV by both PCR techniques, there was concordance of results in 38 (90%). Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells.

PMID: 11891176 [PubMed - indexed for MEDLINE]

Evidence for trafficking of Epstein-Barr virus strains between hairy leukoplakia and peripheral blood lymphocytes.

J Gen Virol. 2002 Feb;83(Pt 2):317-21

Authors: Palefsky JM, Berline J, Greenspan D, Greenspan JS

Hairy leukoplakia (HL), an epithelial lesion found on the side of the tongue in immunocompromised individuals, is characterized by high-level replication of Epstein-Barr virus (EBV) and multiple EBV strains. The source of these strains and their relationship to peripheral blood lymphocyte (PBL) strains has not previously been characterized. Using matched pairs of HL scrapings and PBL from 16 HIV-positive men, variation in EBV strain identity was characterized by detection of a 30 nucleotide deletion of the EBV latent membrane protein (LMP)-1 gene, variation in the LMP-1 repeat region and typing for Epstein-Barr nuclear antigen (EBNA)-2. Multiple EBV strains were found in both the HL and PBL specimens, but 13 of 16 (81%) patients showed evidence of strain identity for at least one strain and analysis of two patients suggested that EBV strains from HL could infect the PBL. Our data are consistent with active trafficking of EBV between these two compartments.

PMID: 11807224 [PubMed - indexed for MEDLINE]

Roles of Epstein-Barr virus glycoproteins gp350 and gp25 in the infection of human epithelial cells.

J Gen Virol. 2001 Oct;82(Pt 10):2373-83

Authors: Maruo S, Yang L, Takada K

Epstein-Barr virus (EBV) is associated with various epithelial malignancies such as nasopharyngeal carcinoma and gastric carcinoma, and causes oral hairy leukoplakia, a productive EBV infection of the differentiated epithelium of the tongue. However, it is not clear by what mechanism EBV infects epithelial cells. We generated a recombinant EBV that expresses enhanced green fluorescent protein in order to monitor EBV entrance into epithelial cells quickly and quantitatively. Using this monitoring system, we examined the roles of gp350 and gp25 in EBV infection of epithelial cells by utilizing soluble forms of the gp350 and gp25 proteins. EBV infection of three of four examined epithelial cell lines, 293, NU-GC-3 and Lovo, was almost completely blocked by pretreatment of cells with a soluble form of gp350 (designated gp350Ig), and this blockage was dependent on the CD21-binding region of gp350. On the other hand, infection of the other epithelial cell line, AGS, was not inhibited at all by pretreatment with gp350Ig. Moreover, we found that a soluble form of gp25 (designated gp25Ig) preferentially bound to epithelial cells rather than B cells, and pretreatment of cells with gp25Ig substantially blocked EBV infection of some epithelial cells. These results indicate the existence of two distinct pathways in EBV infection of epithelial cells, a gp350-dependent pathway and a gp350-independent pathway, and that gp25 can play a role in the infection of some epithelial cells.

PMID: 11562531 [PubMed - indexed for MEDLINE]

Avoiding malpractice for nondental conditions. The example of human immunodeficiency virus.

J Am Dent Assoc. 2001 Apr;132(4):499-507

Authors: Grimes RM, Richards E, Flaitz CM

BACKGROUND: Dentists are legally liable for failing to recognize medical conditions that they identify while providing dental care and for failing to refer patients for follow-up care and testing. This article suggests ways to avoid liability using human immunodeficiency virus, or HIV, infection as an example. TYPES OF LITERATURE REVIEWED: The authors conducted a review of the legal literature to determine circumstances that would cause dentists to have legal liability for failing to recognize a medical problem. The authors also conducted a review of the dental literature to identify the most common signs of HIV infection that dentists might see in practice. RESULTS: The legal literature indicates that dentists can be held liable for failing to recognize medical problems, including HIV and acquired immunodeficiency syndrome. The dental literature shows that there are multiple signs and symptoms that indicate the potential for HIV infection to be the underlying cause of many oral diseases. PRACTICE IMPLICATIONS: Dentists should be familiar with the most common oral manifestations of medical conditions that are likely to be identified in the dental office, including those associated with HIV infection. They must recognize medical conditions and arrange for appropriate referral to avoid liability.

PMID: 11315381 [PubMed - indexed for MEDLINE]

Molecular diagnosis of Epstein-Barr virus-related diseases.

J Mol Diagn. 2001 Feb;3(1):1-10

Authors: Gulley ML

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Molecular testing is increasingly important in the diagnosis and monitoring of patients affected by these diseases. In biopsy tissues, molecular detection of EBV-encoded RNA transcripts by in situ hybridization remains the gold standard for proving that a histopathological lesion is EBV-related. EBV-encoded RNA hybridization and EBV LMP1 immunostains are used routinely to detect latent EBV in tissues affected by posttransplant lymphoproliferative disorder (PTLD) or in enlarged nodes from patients with infectious mononucleosis. Traditional serology is the best test for evaluating acute versus remote infection in healthy individuals. High serological titers serve as a tumor marker for some EBV-related malignancies, but titers are not a dependable tumor marker in immunocompromised hosts. EBV viral load testing by quantitative DNA amplification of blood samples is a promising new laboratory test that has proven useful for early diagnosis and monitoring patients with PTLD. Recent studies suggest a role for EBV viral load testing in nasopharyngeal carcinoma, Hodgkin's disease, and AIDS patients with brain lymphoma. Further research is needed to define more fully the clinical utility of viral load tests in the full spectrum of EBV-associated diseases. Gene expression profiling is on the horizon as a means to improve subclassification of EBV-related diseases and to predict response to therapy.

PMID: 11227065 [PubMed - indexed for MEDLINE]

The significance of oral health in HIV disease.

Sex Transm Infect. 2000 Aug;76(4):236-43

Authors: Chapple IL, Hamburger J

PMID: 11026876 [PubMed - indexed for MEDLINE]

Oral hairy leukoplakia. Histopathologic and cytopathologic features of a subclinical phase.

Am J Clin Pathol. 2000 Sep;114(3):395-401

Authors: Dias EP, Rocha ML, Silva J&#xFA;niorA , Spyrides KS, Ferreira SM, Polignano GA, Feijó EC, Da Fonseca EC

Accurate diagnosis of oral hairy leukoplakia (OHL) is important because it may be an early indicator of undiagnosed HIV infection; moreover, it may be a prognostic indicator. Our purpose was to investigate the histopathologic features of subclinical OHL and to evaluate and support the rationale of detecting subclinical OHL with cytopathology. The Epstein-Barr virus (EBV) was detected by immunohistochemistry and in situ hybridization in 4 cases of macroscopically normal lateral borders of tongue mucosa from 8 AIDS necropsies and in none of 8 controls. The histopathologic features were specific when based on nuclear changes: Cowdry type A inclusion, ground glass, and nuclear beading. Smears were obtained from 50 patients with AIDS, without OHL, from the scraping of lateral borders of the tongue. Numerous clusters of the cells were associated with Candida organisms (30% of cases). Nuclear changes were observed in 12 patients (24%) on both sides of the tongue. We describe the histopathologic features of subclinical OHL, and our observations suggest that cytopathology can detect OHL in the subclinical phase.

PMID: 10989640 [PubMed - indexed for MEDLINE]

Hairy leukoplakia: an unusual combination of transforming and permissive Epstein-Barr virus infections.

J Virol. 2000 Aug;74(16):7610-8

Authors: Webster-Cyriaque J, Middeldorp J, Raab-Traub N

Human herpesviruses are characterized by distinct states of infection. Typically in permissive herpesvirus infection, abundant virus production results in cell lysis. In latent transforming Epstein-Barr virus (EBV) infection, viral proteins that induce cell growth are expressed. The immunodeficiency-associated hairy leukoplakia (HLP) lesion is the only pathologic manifestation of permissive EBV infection; however, within HLP, viral proteins characteristic of latent infection have also been detected. In this study, we further analyzed expression of EBV latent genes and investigated their contribution to the unique histologic phenotype of HLP. Coexpression of lytic and transforming viral proteins was detected simultaneously within individual HLP keratinocytes. LMP1 has now been shown to be uniformly expressed in the affected tissue, and it is associated and colocalizes with tumor necrosis factor receptor-associated factor (TRAF) signaling molecules. Effects induced by activated TRAF signaling that were detected in HLP included activation of NF-kappaB and c-Jun terminal kinase 1 (JNK1) and upregulated expression of epidermal growth factor receptor (EGFR), CD40, A20, and TRAFs. This study identifies a novel state of EBV infection with concurrent expression of replicative and transforming proteins. It is probable that both replicative and latent proteins contribute to HLP development and induce many of the histologic features of HLP, such as acanthosis and hyperproliferation. In contrast to other permissive herpesvirus infections, expression of EBV transforming proteins within the permissively infected HLP tissue enables epithelial cell survival and may enhance viral replication.

PMID: 10906215 [PubMed - indexed for MEDLINE]

Expression of Epstein-Barr virus (EBV) transcripts encoding homologues to important human proteins in diverse EBV associated diseases.

Mol Pathol. 1999 Apr;52(2):97-103

Authors: Hayes DP, Brink AA, Vervoort MB, Middeldorp JM, Meijer CJ, van den Brule AJ

AIMS: To examine the expression of Epstein-Barr virus (EBV) transcripts encoding proteins homologous to important human proteins in diverse EBV associated diseases. The proteins were: BHRF1 (homologous to Bcl-2), BDLF2 (homologous to cyclin B1), BARF1 (homologous to intercellular cell adhesion molecule 1 (ICAM-1)), and BCRF1 (viral IL-10 (vIL-10), homologous to human IL-10 (hIL-10)). METHODS: Six cases of oral hairy leukoplakia, seven of Hodgkin's disease, eight of T cell non-Hodgkin's lymphoma, and nine of nasopharyngeal carcinoma were examined at the mRNA level using either the reverse transcriptase polymerase chain reaction (RT-PCR) or nucleic acid sequence based amplification (NASBA). Different primer sets allowed the differentiation by RT-PCR of the latent (Cp/Wp driven) and lytic (Hp driven) transcripts of BHRF1. A specific NASBA reaction was developed for the detection of vIL-10 and BDLF2 transcripts and this was tested initially on cell lines and later on clinical samples. RESULTS: vIL-10 and BDLF2 were expressed almost exclusively in oral hairy leukoplakia, whereas BARF1 transcripts were present in all cases of nasopharyngeal carcinoma, with weak expression in one oral hairy leukoplakia and isolated cases of lymphoid malignancy. Both BHRF1 transcripts were detected across the range of tissues tested, but strong expression of lytic BHRF1 transcripts was seen only in oral hairy leukoplakia. CONCLUSIONS: vIL-10 and BDLF2 transcripts are expressed during productive EBV infection and are unlikely to be important in the pathogenesis of EBV associated malignancies. BARF1 appears to be expressed preferentially during viral latency and is more closely associated with malignant rather than benign epithelial proliferations. The alternative transcripts derived from the BHRF1 open reading frame may have very different roles during latent or productive infection.

PMID: 10474689 [PubMed - indexed for MEDLINE]

Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: novel antiviral mechanism of 5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole.

J Virol. 1999 Sep;73(9):7271-7

Authors: Zacny VL, Gershburg E, Davis MG, Biron KK, Pagano JS

Although a number of antiviral drugs inhibit replication of Epstein-Barr virus (EBV) in cell culture, and acyclovir (ACV) suppresses replication in vivo, currently available drugs have not proven effective for treatment of EBV-associated diseases other than oral hairy leukoplakia. Benzimidazole riboside compounds represent a new class of antiviral compounds that are potent inhibitors of human cytomegalovirus (HCMV) replication but not of other herpesviruses. Here we characterize the effects of two compounds in this class against lytic replication of EBV induced in a Burkitt lymphoma cell line latently infected with EBV. We analyzed linear forms of EBV genomes, indicative of lytic replication, and episomal forms present in latently infected cells by terminal probe analysis followed by Southern blot hybridization as well as the high-molecular-weight unprocessed viral DNA by pulsed-field gel electrophoresis. D-Ribofuranosyl benzimidazole compounds that act as inhibitors of HCMV DNA maturation, including BDCRB (5, 6-dichloro-2-bromo-1-beta-D-ribofuranosyl-1H-benzimidazole), did not affect the accumulation of high-molecular-weight or monomeric forms of EBV DNA in the induced cells. In contrast, the generation of linear EBV DNA as well as precursor viral DNA was sensitive to the L-riboside 1263W94 [5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole]. The 50% inhibitory concentration range for 1263W94 was 0.15 to 1. 1 microM, compared with 10 microM for ACV. Thus, 1263W94 is a potent inhibitor of EBV. In addition, 1263W94 inhibited the phosphorylation and the accumulation of the essential EBV replicative cofactor, early antigen D.

PMID: 10438815 [PubMed - indexed for MEDLINE]

Regulation of Epstein-Barr virus promoters in oral epithelial cells and lymphocytes.

J Virol. 1999 Aug;73(8):6566-72

Authors: Lagenaur LA, Palefsky JM

Hairy leukoplakia (HL) is a proliferative lesion of the tongue that supports abundant Epstein-Barr virus (EBV) replication. Previous work showed high-level expression of the EBV BMRF2 gene in HL. To characterize the regulation of BMRF2 expression in HL, we mapped the 5' ends of the BMRF1 and BMRF2 transcripts and showed that BMRF2 is expressed from a novel internal promoter within the BMRF1 coding region. Mechanisms of BMRF2 regulation were compared in oral epithelial cells and B lymphocytes, as were those of BMRF1 and BDLF3, early and late EBV transcripts, respectively, that are also known to be expressed in HL. Basal activity of the putative BMRF2 promoter was 10-fold higher in HSC-3 epithelial cells than in B lymphocytes. The BMRF2 and the BDLF3 promoters were responsive to induction by phorbol ester, but unlike the BMRF1 promoter, they were not responsive to BZLF1 transactivation. By mutational analysis, the major activity of the BMRF2 promoter mapped to a 50-bp region, which includes a TATA-like element and a GC box. The BMRF2 promoter may be regulated differentially from the BMRF1 promoter and more closely resembles that of BDLF3. This novel BMRF2 promoter likely belongs to a class of viral promoters that is more responsive to mechanisms known to induce epithelial cell differentiation, consistent with its high level of expression in HL.

PMID: 10400753 [PubMed - indexed for MEDLINE]

CD21-Dependent infection of an epithelial cell line, 293, by Epstein-Barr virus.

J Virol. 1999 Mar;73(3):2115-25

Authors: Fingeroth JD, Diamond ME, Sage DR, Hayman J, Yates JL

Epstein-Barr virus (EBV) is invariably present in undifferentiated nasopharyngeal carcinomas, is found sporadically in other carcinomas, and replicates in the differentiated layer of the tongue epithelium in lesions of oral hairy leukoplakia. However, it is not clear how frequently or by what mechanism EBV infects epithelial cells normally. Here, we report that a human epithelial cell line, 293, can be stably infected by EBV that has been genetically marked with a selectable gene. We show that 293 cells express a relatively low level of CD21, that binding of fluorescein-labeled EBV to 293 cells can be detected, and that both the binding of virus to cells and infection can be blocked with antibodies specific for CD21. Two proteins known to form complexes with CD21 on the surface of lymphoid cells, CD35 and CD19, could not be detected at the surface of 293 cells. All infected clones of 293 cells exhibited tight latency with a pattern of gene expression similar to that of type II latency, but productive EBV replication and release of infectious virus could be induced inefficiently by forced expression of the lytic transactivators, R and Z. Low levels of mRNA specific for the transforming membrane protein of EBV, LMP-1, as well as for LMP-2, were detected; however, LMP-1 protein was either undetectable or near the limit of detection at less than 5% of the level typical of EBV-transformed B cells. A slight increase in expression of the receptor for epidermal growth factor, which can be induced in epithelial cells by LMP-1, was detected at the cell surface with two EBV-infected 293 cell clones. These results show that low levels of surface CD21 can support infection of an epithelial cell line by EBV. The results also raise the possibility that in a normal infection of epithelial cells by EBV, the LMP-1 protein is not expressed at levels that are high enough to be oncogenic and that there might be differences in the cells of EBV-associated epithelial cancers that have arisen to allow for elevated expression of LMP-1.

PMID: 9971794 [PubMed - indexed for MEDLINE]

Diagnosing HIV-related disease: using the CD4 count as a guide.

J Gen Intern Med. 1998 Feb;13(2):131-6

Authors: Jung AC, Paauw DS

OBJECTIVE: To summarize current information on the relation between CD4 counts and the risk of different HIV-related diseases. MEASUREMENTS AND MAIN RESULTS: MEDLINE search of English language articles between 1985 and 1996 using the medical subject heading (MeSH) term "CD4 lymphocyte count" and searches using key words of multiple HIV-related diseases were conducted. Some HIV-related diseases can be stratified to different CD4 count levels. Regardless of their CD4 count, HIV-infected patients are susceptible to sinusitis, Kaposi's sarcoma, community-acquired pneumonia, and oral hairy leukoplakia. In advanced HIV, when CD4 is below 200/mm3, Pneumocystis carinii pneumonia, toxoplasmosis, progressive multifocal leukoencephalopathy, Mycobacterium avium complex, molluscum contagiosum, and bacillary angiomatosis all increase in incidence. In very advanced HIV disease, when CD4 counts are below 50/mm3, patients are at risk of pseudomonas pneumonia, cytomegalovirus retinitis, central nervous system lymphoma, aspergillosis, and disseminated histoplasmosis.

PMID: 9502375 [PubMed - indexed for MEDLINE]

Expression of Epstein-Barr virus BMRF-2 and BDLF-3 genes in hairy leukoplakia.

J Gen Virol. 1997 Dec;78 ( Pt 12):3361-70

Authors: Pe&#xF1;aranda ME, Lagenaur LA, Pierik LT, Berline JW, MacPhail LA, Greenspan D, Greenspan JS, Palefsky JM

The high level of Epstein-Barr virus (EBV) replication found in hairy leukoplakia (HL) provides a unique opportunity to study EBV expression in the oral epithelium. Screening of a cDNA library from an HL biopsy revealed expression of two genes not previously described in vivo: BMRF-2 and BDLF-3. Sequence analysis of the cDNAs demonstrated several nucleotide changes from the B95-8 sequence. In all six different HL strains studied, only one amino acid change was found in BMRF-2 relative to B95-8 and two amino acid changes were found in the BDLF-3 ORF. mRNA expression of both genes was localized to the lower prickle cell layer of the tongue epithelium. BMRF-2 protein expression was primarily detected in the cell nuclei of the upper prickle cell layer; immunoelectron microscopy revealed that BMRF-2 was associated with the nuclear chromatin. BDLF-3 protein expression was observed in the perinuclear space and cytoplasm of the prickle cells. BDLF-3 has recently been identified as a virion-associated protein, but the functions of BMRF-2 and BDLF-3 have not been elucidated.

PMID: 9400989 [PubMed - indexed for MEDLINE]

Identification of a novel protein encoded by the BamHI A region of the Epstein-Barr virus.

J Virol. 1997 Apr;71(4):2765-71

Authors: Fries KL, Sculley TB, Webster-Cyriaque J, Rajadurai P, Sadler RH, Raab-Traub N

An unusual set of 3' coterminal, spliced mRNAs transcribed through the BamHI A fragment have been previously identified in nasopharyngeal carcinoma (NPC) tissues. These RNAs have also been detected at low levels in Burkitt's lymphoma (BL) cell lines and Epstein-Barr virus (EBV)-transformed lymphocytes. Sequence analyses of clones from a cDNA library derived from the C15 NPC tumor indicated that the primary transcripts are differentially spliced, giving rise to a family of related transcripts, all of which encompass the BARF0 open reading frame (ORF) at the 3' end of the transcripts. One cDNA was identified that extended the BARF0 ORF at the 5' end, forming the RK-BARF0 ORF. In this study, a rabbit antiserum to a synthetic peptide representing an amino acid sequence encoded by the BARF0 ORF was prepared. This antiserum detected a glutathione S-transferase-BARF0 fusion protein and both BARF0 and RK-BARF0 proteins expressed from transfected constructs in H1299 cells. The serum also immunoprecipitated the 20-kDa BARF0 and 30-kDa RK-BARF0 in vitro-translated proteins. Immunoblot analyses identified a protein doublet of 30 and 35 kDa in all of the EBV-infected cell lines tested. Cellular fractionation studies revealed that the proteins were membrane associated. The sizes of the proteins detected in cell lines and their association with membranes suggests that they are likely encoded by the RK-BARF0 transcript, which is predicted to contain a membrane localization signal. The proteins were also detected in protein extracts prepared from NPC biopsies and a BL biopsy but not from hairy leukoplakia, a permissive EBV infection. These results reveal that the rightward RNA transcripts from the BamHI A region of EBV encode one or more proteins that are expressed in latently infected cells and in tumor tissue.

PMID: 9060630 [PubMed - indexed for MEDLINE]

Development of oral lesions in human immunodeficiency virus-infected transfusion recipients and hemophiliacs.

Am J Epidemiol. 1997 Jan 15;145(2):164-74

Authors: Hilton JF, Donegan E, Katz MH, Canchola AJ, Fusaro RE, Greenspan D, Greenspan JS

The authors used multivariate repeated-measures transition models to identify risk factors for two oral lesions related to human immunodeficiency virus (HIV)-candidiasis and hairy leukoplakia-in 152 HIV-infected blood transfusion recipients and hemophiliacs. Subjects were examined for occurrences of these lesions every 6 months from July 1985 through March 1993, yielding 1,076 study visits. It was found that, after adjustment for the CD4:CD8 T-lymphocyte ratio, patients with a history of candidiasis in the previous 18 months were at high risk of lesion recurrence. This risk increased with the number of prior episodes and with the recency of the episode(s). A history of hairy leukoplakia was less predictive of persistence of that lesion after adjustment for significant risk factors (including candidiasis and use of antifungal agents at the current examination, a low CD4:CD8 cell ratio, and age less than 40 years). The authors also found a high coprevalence of candidiasis and hairy leukoplakia in these subjects. These results suggest that HIV-infected patients with oral candidiasis should be carefully monitored for subsequent episodes over the next 12-18 months, and patients with either oral candidiasis or hairy leukoplakia and a low CD4:CD8 cell ratio should be carefully examined for the other type of lesion as well.

PMID: 9006313 [PubMed - indexed for MEDLINE]

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

N Engl J Med. 1995 Aug 17;333(7):408-13

Authors: Kinloch-De Lo&#xEB;s S, Hirschel BJ, Hoen B, Cooper DA, Tindall B, Carr A, Saurat JH, Clumeck N, Lazzarin A, Mathiesen L

BACKGROUND. It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS. To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS. The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS. Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

PMID: 7616989 [PubMed - indexed for MEDLINE]

Oral leukoplakia.

Crit Rev Oral Biol Med. 1995;6(2):147-60

Authors: Sciubba JJ

Leukoplakia has evolved as a clinico-pathologic concept over many years, with the current clinical designation being accepted worldwide. Reflective of the biology of leukoplakia is the concept of cellular atypia and epithelial dysplasia. Adding to a better understanding of leukoplakia in general has been the definition of relevant clinical subsets which, in some cases, includes etiology (snuff), while in other cases a verrucous clinical appearance will suggest a more aggressive anticipated behavior pattern. Tobacco usage, in many of its forms, remains the prime etiologic factor; however, other considerations also apply. More recently, the potential etiologic role of Candida albicans has been stressed, as well as its possible role in carcinogenesis. So-called oral hairy leukoplakia has been defined in relation to a possible Epstein-Barr viral infection, usually in the immunosuppressed patient. Other viruses, human papilloma virus in particular, have been implicated in leukoplakia, while genetic alterations involving tumor suppressor elements (p53) have also been investigated. Finally, the management of this common condition remains a variable and includes local, topical, and systemic therapies such as anti-oxidants, carotenoids, and retinoids.

PMID: 7548621 [PubMed - indexed for MEDLINE]

The Epstein-Barr virus EBNA-2 gene in oral hairy leukoplakia: strain variation, genetic recombination, and transcriptional expression.

J Virol. 1994 Dec;68(12):7918-26

Authors: Walling DM, Perkins AG, Webster-Cyriaque J, Resnick L, Raab-Traub N

Oral hairy leukoplakia (HLP) lesions frequently contain defective Epstein-Barr virus (EBV) genomes with deletions in the EBNA-2 gene that abundantly replicate and persist within the lesion. To characterize these viral strains and recombinant variants, the EBNA-2 gene in EBV DNA from several different HLP biopsy specimens was analyzed. Amplification of EBNA-2 coding sequences by PCR demonstrated the presence in HLP of intact EBNA-2 genes as well as a variety of internally deleted variants of both EBNA-2A and EBNA-2B. Some of the deletion variants evolved within the HLP lesion from intact EBNA-2 genes, while other variants appeared to be transmissible strains that directly infected the lesion. Intrastrain recombination within the HLP lesion also generated variation within the EBNA-2 polyproline region. Cloning and sequencing of HLP cDNA demonstrated transcription from the internally deleted EBNA-2 open reading frame, indicating that these variant genes are expressed in HLP. Comparative analysis of the HLP EBNA-2 sequences confirmed previous findings of EBV coinfection with multiple types and strains. Sequence variation of these wild-type genes demonstrated that EBNA-2A sequences distinguish at least two separate strains and a variety of substrains of EBV type 1. Two of the HLP EBNA-2A sequences contained amino acid changes in a cytotoxic T-cell epitope within an otherwise highly conserved region of the gene. These data indicate that EBV coinfection, strain variation, and recombination within the EBNA-2 gene are common features of HLP and suggest that the expression of internally deleted EBNA-2 variants could contribute to EBV pathogenesis in permissive infection.

PMID: 7966582 [PubMed - indexed for MEDLINE]

Epstein-Barr virus intrastrain recombination in oral hairy leukoplakia.

J Virol. 1994 Dec;68(12):7909-17

Authors: Walling DM, Raab-Traub N

In laboratory lymphoblastoid cell lines and in natural human infections, Epstein-Barr virus (EBV) strains have been identified by DNA restriction fragment length polymorphisms of the BamHI H fragment. Multiple, heterogeneous BamHI H fragments have been detected in oral hairy leukoplakia (HLP), raising the question of EBV coinfection with multiple strains. To investigate whether the heterogeneous BamHI H fragments represent different EBV strains or recombinant variants of the same strain, EBV DNA from HLP lesions was analyzed to characterize the viral strains and determine the source of possible recombinant variants. Clones of heterogeneous BamHI H fragments from a single HLP lesion were determined to have strain identity on the basis of sequence identity of the EBNA-2 genes. Intrastrain homologous recombination within the IR2 internal repeat region and nonhomologous recombination of other sequences accounted for the heterogeneity of the BamHI H fragments. PCR amplification from additional HLP specimens detected similar recombinant variants. A possible example of site-specific recombination joining the BamHI Y portion of the EBNA-2 gene to sequences within the BamHI S fragment was also detected in multiple HLP specimens. These data indicate that intrastrain recombination during productive replication confounds the use of restriction fragment length polymorphism analysis of the BamHI Y and H fragments to identify EBV strains in HLP. In patients with permissive epithelial EBV infections, EBV strains could be more accurately distinguished by sequence identity or divergence within known regions of genetic strain variation.

PMID: 7966581 [PubMed - indexed for MEDLINE]

Detection and characterization of Epstein-Barr virus in clinical specimens.

Am J Pathol. 1994 Aug;145(2):239-52

Authors: Ambinder RF, Mann RB

Epstein-Barr virus (EBV) is associated with a wide spectrum of benign and malignant diseases. Recent additions to the list include oral hairy leukoplakia; a subset of Hodgkin's lymphomas, particularly those with mixed cellularity histology or those occurring in underdeveloped countries; a subset of diffuse large cell/immunoblastic lymphoma in the immunocompromised, particularly primary central nervous system lymphoma; a subset of peripheral T cell lymphomas; and a subset of gastric carcinomas, particularly undifferentiated carcinomas. There are several distinctive aspects of the biology of the virus that are important in investigations of virus in clinical specimens. The presence of repeated elements in the genome facilitates detection of viral nucleic acids by a variety of hybridization techniques as well as the characterization of the clonality of virus-infected tissues. Latent viral infection is associated with several different patterns of viral gene expression in infected cells. Latent gene products are important because of their growth-regulating and -transforming properties as well as the potent cytotoxic T cell response they elicit. The abundant expression of the EBER RNA transcripts makes possible the sensitive detection of latent infection in EBV-associated tumors. Lytic infection can be inhibited by antiviral nucleoside analogues. Two lytic gene products are of special interest because of their homology to the cellular proteins BCL-2 and interleukin-10. Two viral biotypes or strains with different properties in terms of lymphocyte immortalization and transformation have recently been characterized. Current evidence suggests a differential biotype association with particular malignancies. Characterization of the association of EBV with various disease processes promises to be important for diagnosis and treatment as well as for a better understanding of the epidemiology and pathogenesis of these diabetes.

PMID: 8053485 [PubMed - indexed for MEDLINE]

Oral lesions among HIV-infected hemophiliacs. A study of 54 patients.

Haematologica. 1994 Mar-Apr;79(2):148-53

Authors: Ficarra G, Chiodo M, Morfini M, Longo G, Orsi A, Piluso S, Rafanelli D

BACKGROUND. HIV-infected individuals develop a large variety of oral manifestations. This study was designed to assess the prevalence and types of oral lesions among HIV-positive hemophiliacs. MATERIALS AND METHODS. A study population of 54 hemophiliacs was evaluated from February, 1987 to March, 1992 in order to analyze types, prevalence and relationships to clinical stages of HIV-related oral lesions. Thirty-six (67%) of the group of patients were HIV seropositive. The remaining 18 tested negative to HIV during the observation period. RESULTS. The majority of patients suffered from hemophilia A. One patient was also bisexual and two were also intravenous drug abusers. Analysis of patient stage revealed that half had a CD4+ T-lymphocyte count over 0.5 x 10(9)/L cells, 10 between 0.2 and 0.499 x 10(9)/L and 8 showed a count lower than 200 x 10(9)/L. Oral lesions were recorded in 18 (50%) HIV-seropositive hemophiliacs. No oral lesions were observed among the HIV-seronegative hemophiliacs. Advanced stage of immunosuppression and presence of oral lesions were significantly associated (p = 0.040). Candidiasis was the most common disturbance, followed by hairy leukoplakia. Oral herpes simplex infection, necrotizing gingivitis and facial herpes zoster were found in a small number of patients. Those with oral lesions showed a lower median CD4+ T lymphocyte count (0.209 x 10(9)/L cells; range 0.008 to 0.615) when compared to the ones without oral lesions (median CD4+ count was 0.539 x 10(9)/L cells; range 0.042 to 1.180; p = 0.002). CONCLUSIONS. HIV-seropositive hemophiliacs may develop oral lesions during the course of their disease. Candidiasis and hairy leukoplakia are among the most common manifestations. A careful oral examination should be included in the clinical evaluation of all HIV-infected hemophiliacs.

PMID: 8063262 [PubMed - indexed for MEDLINE]

Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. The European-Australian Collaborative Group.

N Engl J Med. 1993 Jul 29;329(5):297-303

Authors: Cooper DA, Gatell JM, Kroon S, Clumeck N, Millard J, Goebel FD, Bruun JN, Stingl G, Melville RL, Gonz&#xE1;lez-Lahoz J

BACKGROUND. Zidovudine therapy is of benefit in the treatment of symptomatic and asymptomatic human immunodeficiency virus (HIV) infection in persons with CD4+ cell counts of less than 500 per cubic millimeter. The efficacy, safety, and duration of benefit of zidovudine in those with 500 or more CD4+ cells per cubic millimeter are uncertain. METHODS. In a double-blind, placebo-controlled trial, 993 patients with asymptomatic HIV infection and CD4+ cell counts above 400 per cubic millimeter were randomly assigned to receive zidovudine (500 mg twice daily) or placebo for three years. The primary end point was progression of disease, as defined by the development of Centers for Disease Control and Prevention (CDC) group IV disease (including recurrent oral candidiasis, hairy leukoplakia, or progressive diarrhea) or two CD4+ cell counts below 350 per cubic millimeter. This outcome measure was changed from the original end point of the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex to reflect changes in recommendations for management. The study was terminated after the first interim analysis. RESULTS. Disease progression was significantly less frequent in the zidovudine group (relative risk, 0.56; 95 percent confidence interval, 0.43 to 0.75; P < 0.001 by the log-rank test). The probability of disease progression at two years was 0.19 with zidovudine, as compared with 0.34 with placebo (95 percent confidence interval for the difference, -0.21 to -0.08). Progression to CDC group IV disease was reduced by half in the zidovudine recipients (relative risk, 0.49; P = 0.049) and decline in CD4+ cell counts to below 350 per cubic millimeter was reduced by 40 percent (relative risk, 0.60; P < 0.001). The inclusion of early HIV disease events (oral candidiasis, oral hairy leukoplakia, and herpes zoster) as end points confirmed the effects of zidovudine on the progression of clinical disease (relative risk, 0.55; 95 percent confidence interval, 0.37 to 0.84; P = 0.004). The median duration of treatment was 94 weeks. Severe hematologic or clinical side effects were rare. CONCLUSIONS. Treatment with zidovudine benefits HIV-infected persons with CD4+ cell counts above 400 per cubic millimeter. Despite the use of doses larger than those now generally prescribed, zidovudine was well tolerated for up to three years by most of our patients.

PMID: 8100611 [PubMed - indexed for MEDLINE]

Epstein-Barr virus-related oral T-cell lymphoma associated with human immunodeficiency virus immunosuppression.

Blood. 1993 Jun 15;81(12):3350-6

Authors: Thomas JA, Cotter F, Hanby AM, Long LQ, Morgan PR, Bramble B, Bailey BM

Epstein-Barr virus (EBV) is generally held to infect B cells and epithelial cells, although there are now reports of EBV infection in normal T cells and neoplastic T-cell diseases. In patients with human immunodeficiency virus (HIV) infection, EBV is associated with the benign epithelial lesion, hairy leukoplakia, and has been reported in up to 80% of acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma. This study shows the presence of EBV in malignant oral T-cell lymphoma in three AIDS patients, two of whom had concurrent manifestation of hairy leukoplakia. The T-cell lineage of the tumor cells was determined by positive immunophenotyping for T-cell markers and lack of B-cell or nonhematopoietic (cytokeratin) determinants. All tumors contained monoclonal T-cell populations shown by polymerase chain reaction, which showed amplification of T-cell receptor gamma chain DNA without evidence of Ig heavy chain gene rearrangement. Furthermore, these lesions showed the presence of EBV DNA and expression of EBV latent gene products in the tumor cells. EBV involvement in AIDS-related T-cell lymphoma has not been widely reported and may represent a further manifestation of opportunistic EBV infection arising in the HIV-immunocompromised host.

PMID: 8389615 [PubMed - indexed for MEDLINE]