Five distinct Epstein-Barr virus (EBV)-determined nuclear antigens (EBNA-1 to EBNA-5) were recently identified. Antibody responses to these antigens could conceivably differ, and thus prove of ...serodiagnostic value, in EBV-associated disease processes. As a first step, murine or human cell lines transfected with appropriate EBV DNA fragments and stably expressing either EBNA-1 or EBNA-2 were used to determine the frequency and time of emergence of antibodies to these two antigens in the course of acute and chronic infectious mononucleosis (IM) and to assess their titers in so-called chronic active EBV infections. Following IM, antibodies to EBNA-2 arose first and, after reaching peak titers, declined again in time to lower persistent or even nondetectable levels. Antibodies to EBNA-1 emerged several weeks or months after anti-EBNA-2 and gradually attained the titers at which they persisted indefinitely. The ratios between the anti-EBNA-1 and anti-EBNA-2 titers therefore were generally well below 1.0 during the first 6-12 months after IM and turned to well above 1.0 during the second year. In clear cases of chronic IM, the inversion of this ratio was delayed or prevented. In the less well-defined chronic EBV infections, low ratios were observed in only some of the patients. Because many of these illnesses were not ushered in by a proven IM and often showed EBV-specific antibody profiles within the normally expected range, a causal role of the virus in these cases remains doubtful.
A rapid, sensitive indirect immunofluorescence assay has been developed for detection of antibodies to the acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV). The human T-cell ...line HUT-78 was chronically infected with ARV-2 and used to detect antibodies to virus-specific cytoplasmic antigens. Because the helper T-cell marker Leu-3 is substantially reduced in this cell line after ARV infection, it appears to be an important receptor for virus infection. Nearly all patients with AIDS and most cases with related conditions showed antibodies against ARV. Some healthy individuals in risk groups for developing AIDS also had antibodies to the agent. In contrast, no antibodies to the virus were found in any individuals outside the risk groups for developing AIDS or with diseases other than those associated with AIDS. The titers of antibodies to ARV and to Epstein-Barr virus varied independently from each other. The level of anti-ARV antibodies in a patient's serum was found to reflect the severity of the disease; it was lower in individuals with more severe manifestations. Taken together, these data support the role of ARV in AIDS and its related disorders.
Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, ...cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.
Thirty-one patients with clinical and laboratory diagnoses of infectious mononucleosis who had had symptoms for seven or fewer days were randomized for intravenous treatment with acyclovir (10 mg/kg) ...or placebo at 8-hr intervals for seven days in a doubleblind trial. Clinical signs and symptoms were registered, and excretion of virus in the saliva as well as antibody responses in sera and saliva were assessed before, during, and at reguIarintervals in the six months after treatment. Acyclovir significantly (P < .001), but reversibly, inhibited oropharyngeal sheclclingqf Epstein-Barr virus. The humoral and cellular immune responses, however, did not differ between the two groups; nor did the development of viral latency. There were no significant (P >.05) differences in individual clinical symptoms or in laboratory parameters between the two groups; however, when data concerning duration of fever, weight loss, tonsillar swelling, pharyngitis, and self-assessment by the patient were combined, a significant (P ⩽ .01) effect of treatment with acyclovir was evident.
The expression of Epstein-Barr virus (EBV)-determined antigens associated with growth-transformation of B cells was studied by immunoblotting with human sera from healthy donors. Four antigens were ...detected in EBV-carrying cell lines and in B lymphocytes early after infection with the transforming B95-8 substrain of virus. They were not found in uninfected cells, nor could they be demonstrated with sera lacking antibodies to EBV antigens. All four antigens were nuclear. Each of them varied in size in the different cell lines. The two antigens with the lowest molecular weight were identified as EBV-determined nuclear antigens (EBNAs) 1 and 2. The two high molecular weight antigens (140-160 kDa and 150-180 kDa, respectively) were detected with 6 of 16 EBV antibody-positive sera. These proteins appeared to be antigenically unrelated to each other and to EBNAs 1 and 2 and were designated EBNAs 3 and 4. Like EBNAs 1 and 2, they bound to double- and single-stranded DNA in vitro.
The frequencies and levels of antibodies to Epstein-Barr virus (EBV)-specific antigens were determined in paired sera and synovial fluids from patients with rheumatoid arthritis (RA) and in sera from ...patients with other connective tissue diseases; i.e., systemic lupus erythematosus, progressive systemic sclerosis, and osteoarthritis (OA). The specimens were also tested for the presence of antibodies to RA-associated nuclear antigen. Compared to healthy controls, the patients' sera showed increased frequencies of elevated antibody titers (>/=320) to Epstein-Barr viral capsid antigen, a correspondingly enhanced (twofold to threefold) geometric mean titer, and an increased frequency of antibodies at elevated titers (>/=10), usually to the restricted component and rarely the diffuse component of the early antigen complex. Levels of antibody to the EBV-associated nuclear antigen were within the normal range. Enhancement of antibody titers was more pronounced in seropositive RA patients (i.e., positive for rheumatoid factor) than in those who were not. Enhancement was also found in systemic lupus erythematosus and progressive systemic sclerosis. Antibody to RA-associated nuclear antigen was detected at an increased frequency only in the group of seropositive RA patients (90%), as compared to 8-15% in the other connective tissue diseases and 6-8% in healthy controls. The antibody titers in the synovial fluids equaled or were at most twofold higher or lower than those in the sera. In addition, levels of EBV-specific antibodies were studied serially over a period of 6-10 mo in patients with RA and OA. Parameters of disease activity were determined and compared to antibody levels. EBV-specific antibodies in sera of OA patients remained constant and within normal limits throughout the study. Although EBV-specific antibodies were often elevated in RA patients, they also remained constant, with the exception of three patients, who showed gradual increases in one of the four antibodies, which did not correlate with disease activity.
We evaluated immune functions in 16 patients with chronic active Epstein-Barr virus (EBV) infection (chronic infectious mononucleosis). Chronic infectious mononucleosis is an illness characterized ...primarily by chronic and occasionally disabling fatigue and other constitutional complaints, only sometimes beginning with an episode of acute infectious mononucleosis, and associated with an abnormal pattern of serum antibodies to EBV. In these patients, the frequency of circulating EBV-infected B cells that manifested spontaneous outgrowth in vitro was comparable to that found in EBV-seropositive normals, and the levels of EBV-specific suppressor activity were also normal. Upon stimulation with polyclonal activators, unseparated cells from these patients produced a relatively normal number of immunoglobulin-secreting cells. However, when purified T cells from these patients were mixed with normal mononuclear cells in co-culture, immunoglobulin production was strikingly suppressed. The degree of this T cell suppression correlated directly with the abnormally elevated titer of antibody to the early antigens of EBV. Interestingly, during normal convalescence from acute EBV-induced infectious mononucleosis a period is also seen during which T cells suppress the response of allogeneic but not autologous cells. Thus, from an immunologic viewpoint, patients with chronic active EBV infection appear "frozen" in a state typically found only briefly during the convalescence from acute EBV infection.
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