JOURNAL
OF
CLINICAL MICROBIOLOGY, Feb. 1990,
p.
Vol. 28, No. 2
211-215
0095-1137/90/020211-05$02.00/0 Copyright © 1990, American Society for Microbiology
Effect of Primary Epstein-Barr Virus Infection on Human Herpesvirus 6, Cytomegalovirus, and Measles Virus Immunoglobulin G Titers ANNIKA LINDE,'* EVA FRIDELL,1 HELENA DAHL,' JAN ANDERSSON,2 PETER BIBERFELD,3 AND BRITTA WAHREN' Department of Virology, National Bacteriological Laboratory, S-105 21 Stockholm,' Department of Infectious Diseases, Danderyd Hospital, S-182 88 Danderyd3 and Immunopathology Laboratory, Department of Pathology, Karolinska Institute, S-104 0 Stockholm,3 Sweden Received 17 July 1989/Accepted 23 October 1989
Immunoglobulin G antibody titers to human herpesvirus 6 (HHV-6), measles virus, and cytomegalovirus (CMV) were examined in serum samples from 31 patients with Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM). Sera were drawn sequentially from the same patients c7 days until 3 years after onset of IM. In seropositive patients, there was a significant decrease with time after IM of the immunoglobulin G titers to the three viruses in the majority of patients; HHV-6 IgG titers decreased in 80%, measles virus IgG titers decreased in 75%, and CMV IgG titers decreased in 67%. Four patients contracted CMV infection during the observation period after IM. In these, HHV-6 IgG titers increased, while EBV and measles virus IgG titers remained essentially stationary. Polyclonal B-cell stimulation during IM is suggested to augment antiviral titers in general, but the increases of HHV-6 IgG titers during EBV and CMV infections may also be due to selective stimulation of memory B cells by related antigens or to reactivation of HHV-6 during infection with these herpesviruses.
acyclovir (ACV) treatment of IM (1). For 7 days, fifteen patients received ACV and sixteen were placebo treated. In all patients, heterophile antibodies were detected. Serologically, all patients had EBV VCA IgG and IgM but no EBV nuclear antigen antibodies in their acute serum samples. The serological assays were performed at the National Bacteriological Laboratory (Stockholm, Sweden) and by the late Werner Henle, Children's Hospital of Philadelphia and School of Medicine, University of Pennsylvania, Philadelphia. Spontaneous outgrowth of EBV-transformed cells and high titers of EBV in saliva were found in all patients admitted to the study. Serum samples were drawn at c7 days, 28 days, 90 days, 180 days, 2 years, and 3 years after onset of IM. Of the 31 patients, 7 and 15 could not be reached or were not willing to donate samples at 2 and 3 years after IM, respectively. No differences in specific EBV titers were noted at any time point when the ACV- and placebo-treated groups were compared. Since ACV has little inhibitory effect on HHV-6 in vivo (17), it seems unlikely that the HHV-6 titers should be affected by ACV treatment. Serum samples from 37 healthy EBV-seropositive individuals without a history of IM within 5 years before sampling were examined concomitantly with the samples from the IM patients as a control. Methods for titrations of specific antibodies. Immunofluorescence assays (IFA) were used for EBV VCA and HHV-6 IgG (9, 10). For EBV VCA, slides with acetone-fixed cells from an EBV-producing P3HR-1 cell line were used. The HHV-6 virus was propagated in the HSB-2 continuous T-cell line. Both the HHV-6 virus and the HSB-2 cell fine were kindly donated by S. Z. Salahuddin and R. C. Gallo of the National Institutes of Health, Bethesda, Md. (16). HSB-2 cells were infected for 3 days with medium from 50 to 90% HHV-6-infected HSB-2 cells, after which smears were made and the slides were fixed in acetone. Five to ten percent of
The interpretation of herpesvirus serology is sometimes complicated by increases in immunoglobulin G (IgG) to heterologous viruses. This is well known for varicella-zoster and herpes simplex virus infections, and increased titers of IgG to human herpesvirus 6 (HHV-6) during infections with other herpesviruses have also been noted (10, 11). In Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections, measurable IgM to both viruses is also found (13). These reactivities may emerge from truly cross-reactive antibodies, reactivation of the heterologous virus, selective stimulation of memory B cells by related antigens, or polyclonal B-cell stimulation during the viral infection. EBV is a potent B-cell-stimulating agent. Appearance of IgM antibodies with various specificities during primary EBV infection is well known, but the effect of EBV infection on levels of specific IgG antibodies has not been thoroughly studied. At the onset of infectious mononucleosis (IM), antibody levels to the viral capsid antigen (VCA) normally have reached their peak. It is likely that other antiviral IgG increases due to EBV-induced polyclonal B-cell stimulation likewise have taken place. Increases in IgG between acuteand convalescent-phase samples as the result of a polyclonal stimulation are in that case difficult to measure. We therefore chose to study antiviral IgG titers in serum samples drawn sequentially from the same patients
OF
CLINICAL MICROBIOLOGY, Feb. 1990,
p.
Vol. 28, No. 2
211-215
0095-1137/90/020211-05$02.00/0 Copyright © 1990, American Society for Microbiology
Effect of Primary Epstein-Barr Virus Infection on Human Herpesvirus 6, Cytomegalovirus, and Measles Virus Immunoglobulin G Titers ANNIKA LINDE,'* EVA FRIDELL,1 HELENA DAHL,' JAN ANDERSSON,2 PETER BIBERFELD,3 AND BRITTA WAHREN' Department of Virology, National Bacteriological Laboratory, S-105 21 Stockholm,' Department of Infectious Diseases, Danderyd Hospital, S-182 88 Danderyd3 and Immunopathology Laboratory, Department of Pathology, Karolinska Institute, S-104 0 Stockholm,3 Sweden Received 17 July 1989/Accepted 23 October 1989
Immunoglobulin G antibody titers to human herpesvirus 6 (HHV-6), measles virus, and cytomegalovirus (CMV) were examined in serum samples from 31 patients with Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM). Sera were drawn sequentially from the same patients c7 days until 3 years after onset of IM. In seropositive patients, there was a significant decrease with time after IM of the immunoglobulin G titers to the three viruses in the majority of patients; HHV-6 IgG titers decreased in 80%, measles virus IgG titers decreased in 75%, and CMV IgG titers decreased in 67%. Four patients contracted CMV infection during the observation period after IM. In these, HHV-6 IgG titers increased, while EBV and measles virus IgG titers remained essentially stationary. Polyclonal B-cell stimulation during IM is suggested to augment antiviral titers in general, but the increases of HHV-6 IgG titers during EBV and CMV infections may also be due to selective stimulation of memory B cells by related antigens or to reactivation of HHV-6 during infection with these herpesviruses.
acyclovir (ACV) treatment of IM (1). For 7 days, fifteen patients received ACV and sixteen were placebo treated. In all patients, heterophile antibodies were detected. Serologically, all patients had EBV VCA IgG and IgM but no EBV nuclear antigen antibodies in their acute serum samples. The serological assays were performed at the National Bacteriological Laboratory (Stockholm, Sweden) and by the late Werner Henle, Children's Hospital of Philadelphia and School of Medicine, University of Pennsylvania, Philadelphia. Spontaneous outgrowth of EBV-transformed cells and high titers of EBV in saliva were found in all patients admitted to the study. Serum samples were drawn at c7 days, 28 days, 90 days, 180 days, 2 years, and 3 years after onset of IM. Of the 31 patients, 7 and 15 could not be reached or were not willing to donate samples at 2 and 3 years after IM, respectively. No differences in specific EBV titers were noted at any time point when the ACV- and placebo-treated groups were compared. Since ACV has little inhibitory effect on HHV-6 in vivo (17), it seems unlikely that the HHV-6 titers should be affected by ACV treatment. Serum samples from 37 healthy EBV-seropositive individuals without a history of IM within 5 years before sampling were examined concomitantly with the samples from the IM patients as a control. Methods for titrations of specific antibodies. Immunofluorescence assays (IFA) were used for EBV VCA and HHV-6 IgG (9, 10). For EBV VCA, slides with acetone-fixed cells from an EBV-producing P3HR-1 cell line were used. The HHV-6 virus was propagated in the HSB-2 continuous T-cell line. Both the HHV-6 virus and the HSB-2 cell fine were kindly donated by S. Z. Salahuddin and R. C. Gallo of the National Institutes of Health, Bethesda, Md. (16). HSB-2 cells were infected for 3 days with medium from 50 to 90% HHV-6-infected HSB-2 cells, after which smears were made and the slides were fixed in acetone. Five to ten percent of
The interpretation of herpesvirus serology is sometimes complicated by increases in immunoglobulin G (IgG) to heterologous viruses. This is well known for varicella-zoster and herpes simplex virus infections, and increased titers of IgG to human herpesvirus 6 (HHV-6) during infections with other herpesviruses have also been noted (10, 11). In Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections, measurable IgM to both viruses is also found (13). These reactivities may emerge from truly cross-reactive antibodies, reactivation of the heterologous virus, selective stimulation of memory B cells by related antigens, or polyclonal B-cell stimulation during the viral infection. EBV is a potent B-cell-stimulating agent. Appearance of IgM antibodies with various specificities during primary EBV infection is well known, but the effect of EBV infection on levels of specific IgG antibodies has not been thoroughly studied. At the onset of infectious mononucleosis (IM), antibody levels to the viral capsid antigen (VCA) normally have reached their peak. It is likely that other antiviral IgG increases due to EBV-induced polyclonal B-cell stimulation likewise have taken place. Increases in IgG between acuteand convalescent-phase samples as the result of a polyclonal stimulation are in that case difficult to measure. We therefore chose to study antiviral IgG titers in serum samples drawn sequentially from the same patients
