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Journal of Clinical Microbiology, March 2001, p. 959-963, Vol. 39, No. 3
Department of Infectious Diseases, Imperial
College School of Medicine, Hammersmith Campus, London W12
ONN,1 and Department of Virology, Royal
Free and University College Medical School, London W1T
4JF,2 United Kingdom
Received 14 August 2000/Returned for modification 6 November
2000/Accepted 22 December 2000
A human herpesvirus 7 (HHV-7) indirect immunofluorescence antibody
avidity test was developed and used with an existing human herpesvirus
6 (HHV-6) antibody avidity test to detect and distinguish low-avidity
antibodies to HHV-6 and HHV-7 and hence the respective primary
infections. With sera from 269 British children aged 0 to 179 weeks,
the tests showed that most (10 of 98 serum samples [13%]) HHV-6
low-avidity antibody was found in the first year of life, whereas for
HHV-7, most (18 of 101 serum samples [20%]) HHV-7 low-avidity
antibody was found in the second year of life. Five children had
low-avidity antibodies to both viruses. Of nine Japanese children with
previously serologically proven primary HHV-6 or HHV-7 infections,
eight had low-avidity antibody only to the relevant virus, but one
child had low-avidity antibodies to HHV-6 and HHV-7. The avidity tests
were applied to five British children and further proof of viral
infection was sought by the detection of specific DNA in serum or
plasma, and saliva or cerebrospinal fluid. In two children who had
low-avidity antibody to HHV-7 but who were seronegative for HHV-6, only
HHV-7 was found. Both viruses were detected in one child with
low-avidity HHV-7 antibody and high-avidity HHV-6 antibody. In two
children with low-avidity antibodies to both viruses, HHV-6 and HHV-7
DNAs were found, confirming dual primary infections and excluding
antibody cross-reactivity.
The discovery of human herpesvirus 6 (HHV-6) in 1986 (22) was soon followed by the
identification of the closely related virus HHV-7 (10).
Both viruses belong to the Roseolovirus genus of the
betaherpesvirus subfamily of herpesviruses and show very similar
biological behaviors: (i) after primary infection they are shed in
saliva throughout life (14, 16, 18, 26, 33); (ii) primary
infection with either virus causes exanthem subitum (roseola infantum)
(25, 35), a classical exanthematous disease of childhood;
and (iii) primary infection with either virus has been associated with
childhood neurological illness, particularly febrile convulsions
(12, 27, 28, 32), and the DNAs of both HHV-6
(12) and HHV-7 (20) have been detected in
cerebrospinal fluid. Any study of the relationship between the two
viruses and disease must therefore use diagnostic methods able to
distinguish between primary HHV-6 and primary HHV-7 antibody responses.
Primary infections may be diagnosed by the use of antibody avidity
tests since antibody avidity increases progressively with time after
exposure to an immunogen (8). Tests for antibody avidity
have been applied successfully to sera for the diagnosis of many
different human virus infections (for reviews, see references 11
and 13) and rely on the fact that an agent which denatures protein will disrupt the antigen-antibody reaction preferentially, affecting low-avidity antibody but not high-avidity antibody (15, 21). If antibody avidity is low, this confirms recent primary infection, but if the avidity is high, primary infection must have
occurred in the more distant past.
In this context we had previously successfully developed an HHV-6
antibody avidity test (30) for the diagnosis of primary HHV-6 infection in children with rashes (24). This test
has also been proven to differentiate between a primary HHV-6 antibody response and a secondary HHV-6 antibody response in immunocompromised solid-organ graft recipients (31). The present paper
describes the development and validation of an HHV-7 antibody avidity
test for use in conjunction with the HHV-6 antibody avidity test. The specificities of both these tests were confirmed by the parallel detection of viral DNA in saliva and in some cases serum and/or cerebrospinal fluid.
Samples for antibody testing.
Sera or plasma (from blood
collected by venipuncture or on filter paper after finger prick) from
the following patients were stored at (i) British children under 4 years old.
Sera from children
had been submitted for routine virus investigation between 1987 and
1990 to the Clinical Virology Laboratory, Addenbrooke's Hospital,
Cambridge, United Kingdom. Three hundred twenty-one serum samples from
children aged 0 to 180 weeks were selected and tested previously for
HHV-6 immunoglobulin G (IgG) antibody and avidity (30). Of
these, 269 serum samples, each of which was from a different individual
(112 females, 156 males, and 1 of unknown sex) remained in sufficient
volume to test for HHV-7 IgG antibody and avidity.
(ii) British adults.
Forty serum samples were chosen
randomly from 40 women who had been tested for rubella antibodies at
the Clinical Virology Laboratory, Addenbrooke's Hospital.
(iii) Japanese children with serologically proven primary HHV-6
and HHV-7 infection.
Acute- and convalescent-phase plasma samples
were kindly provided by Y. Asano, Department of Pediatrics, Fujita
Health University School of Medicine, Aichi, Japan. Samples from six
children with primary HHV-6 infection (patients 1 to 6) had been tested
for HHV-6 antibody by a neutralization assay in Japan
(23), and seroconversion for HHV-6 IgG together with the
presence of low-avidity antibody was confirmed in our laboratory (for
full details on patients 1 to 5, see patients 3 to 7, respectively, in
reference 30). Samples from three children with primary
HHV-7 infection (patients 7 to 9) had been tested in Japan for HHV-6
and HHV-7 IgG antibody by an indirect immunofluorescence assay
(37). The ages of the children and the timing of sample
collection (the number of days after the onset of symptoms) were as
follows: 12 months, days 3 and 19; 19 months, days 7 and 60, and 21 months, days 4 and 60, respectively.
(iv) British children referred for diagnosis of HHV-6 and -7 infections.
Plasma or serum from patients 10 to 14 had been
referred to the Diagnostic Virology Laboratory, University College
Hospital, London, United Kingdom, for diagnosis of HHV-6 and HHV-7 infections.
Indirect immunofluorescence tests. (i) HHV-6 and HHV-7
antibodies.
HHV-6 IgG antibody was detected by immunofluorescence
(29). The same method was used to detect HHV-7 IgG
antibody but using the MK strain of HHV-7 (kindly provided by D. A. Clark, Department of Virology, Royal Free and University College
School of Medicine, London, United Kingdom) passaged in Sup-T1 cells.
Serum or plasma samples were tested in doubling dilutions, starting at
a 1 in 10 dilution except for those from patients 10 to 14, for whom the starting dilution was either 1 in 8 or 1 in 16 if blood had been
collected on filter paper and serum had been extracted
(9). Seroconversion was defined as a change from
undetectable antibody to antibody detectable at eight times or more
than the minimum level. An eightfold or greater increase in antibody
titer was considered a significant rise.
(ii) Avidities of HHV-6 and HHV-7 IgG antibodies.
The IgG
tests described above were modified to elute low-avidity antibody with
urea as described previously for HHV-6 (30). Those samples
whose antibody titers were reduced eightfold or greater by urea were
defined as having low avidity, and conversely, sera whose titers were
reduced fourfold or less were defined as having high avidity.
PCR for HHV-6 and HHV-7.
The samples tested had been taken
for diagnostic purposes from the British children referred for
diagnosis of HHV-6 and HHV-7 infections.
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.3.959-963.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Use of Immunoglobulin G Antibody Avidity for
Differentiation of Primary Human Herpesvirus 6 and 7 Infections
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
20°C.
20°C. At the time of
testing the saliva extract was thawed and then centrifuged at 15,000 × g for 5 min. Fifty microliters of supernatant was removed,
boiled for 10 min, cooled immediately on ice, and held briefly at 4°C until required.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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HHV-6 and HHV-7 IgG antibodies and avidities in British children
under 4 years old and adults.
The 269 serum samples from British
children were investigated to confirm the known age of acquisition of
antibodies to the two viruses (26, 30, 36, 37) and to see
whether the distribution of low-avidity antibody coincided with the
expected times of primary infection (6). Figure
1 shows the geometric mean titers of IgG
antibodies to HHV-6 and HHV-7 at 20-week intervals. Titers of antibody
to both viruses reached their lowest point at about 30 weeks and rose
to a maximum at 70 weeks for HHV-6 and at 110 weeks for HHV-7. The sera
from 40 adults, expected to have been infected as children, were
included to determine whether the assays would discriminate between
recent and past infections. All the adult sera contained IgG antibody
to HHV-6 (geometric mean titer [log10], 2.2; 95%
confidence limits, 2.03 to 2.37) and HHV-7 (geometric mean titer
[log10], 2.35; 95% confidence limits, 2.25 to 2.45). For
both groups in whom the antibody titer was 80 or greater, avidity was
also measured. Low-avidity antibody to HHV-6 and/or HHV-7 was found in
the children (54 of 269; 20%) but not in the adults (0 of 40; 0%).
Low-avidity antibody to HHV-6 (13 of 98; 13%) occurred in the highest
proportion of children at 0 to 59 weeks, whereas it occurred in smaller
proportions of children at 60 to 119 weeks (10 of 101; 10%) and 120 to
179 weeks (5 of 70; 7%). In contrast, for HHV-7 the time that the
highest proportion of children had low-avidity antibody was seen later
(incidences, 8 of 98 [8%], 20 of 101 [20%], and 3 of 70 [4%]
for the three time periods, respectively). Five children had
low-avidity antibody to both viruses. Of the 23 children with
low-avidity antibody to HHV-6 but not HHV-7, 1 had no HHV-7 IgG, 15 had
HHV-7 IgG of high avidity, and 7 had HHV-7 IgG at a low titer of 10 or
20. Of the 26 children with low-avidity antibody to HHV-7 but not to
HHV-6, 5 had no HHV-6 IgG, 20 had HHV-6 IgG of high avidity, and 1 had
HHV-6 IgG at a low titer of 20.
|
) and HHV-7 (
) were calculated for 20-week age
intervals from birth to 179 weeks. When the titer was <10 it was given
a nominal value of 5. Bars represent the mean ± twice the
standard error of the mean. The numbers of serum samples tested in each
group were as follows: 0 to 19 weeks, 26; 20 to 39 weeks, 36; 40 to 59 weeks, 36; 60 to 79 weeks, 35; 80 to 99 weeks, 31; 100 to 119 weeks,
35; 120 to 139 weeks, 27; 140 to 159 weeks, 24; 160 to 179 weeks, 19.
HHV-6 and HHV-7 IgG antibodies and avidities in Japanese children with serologically proven primary HHV-6 infection. Seroconversion to HHV-6 IgG was found in patients 1 to 5 (see patients 3 to 7, respectively, in reference 30), and patient 6 showed a 32-fold rise in titer from 10 to 320. Every convalescent-phase sample showed low-avidity antibody. In contrast, seroconversion to HHV-7 IgG with low-avidity antibody was found only in patient 1 (HHV-6 and HHV-7 IgG titers for the acute-phase sample, <10; titers for a convalescent-phase sample, 2,560 for HHV-6 but it was reduced to 40 by urea, and 80 for HHV-7, but it was reduced to <10 by urea). Patient 2 showed a rising titer of HHV-7 IgG, but it was of high avidity (the IgG antibody titers in the acute-phase sample were <10 for HHV-6 and 10 for HHV-7; those for the convalescent-phase sample were 1,280 for HHV-6, which was reduced to 20 by urea, and 80 for HHV-7, which was reduced to 20 by urea). Patient 4 was HHV-7 IgG seronegative, and patients 3, 5, and 6 had very low levels of HHV-7 IgG of 10 or 20.
HHV-6 and HHV-7 IgG antibodies and avidities in Japanese children
with serologically proven primary HHV-7 infection.
All three
Japanese children (patients 7 to 9) showed rising titers of HHV-7 IgG.
In patients 7 and 8 both samples had low-avidity antibody (the HHV-7
IgG antibody titers in the acute-phase samples were 80 and 160, respectively, but both were reduced to <10 by urea; those in the
convalescent-phase samples were 1,280 for both patients, but they were
reduced to 20 and 80 by urea, respectively), whereas in patient 9 the
acute-phase plasma sample showed low-avidity antibody (HHV-7 IgG
antibody titer, 320, but it was reduced to 20 by urea), but the
convalescent-phase plasma sample taken 2 months after disease onset
contained high-avidity antibody (HHV-7 IgG antibody titer, 2,560, but
it was reduced to 320 by urea). In contrast, HHV-6 IgG was of high
titer and high avidity in both acute- and convalescent-phase samples
from all three patients (for the three patients, the HHV-6 IgG antibody
titers in acute-phase samples were 1,280 reduced to 320, 640 reduced to
320, and 5,120 unchanged at 5,120 by urea, respectively; those for the
convalescent-phase samples were 5,120 reduced to 2,560, 640 reduced to
320, and 
20,480 reduced to 10,240 by urea, respectively).
Primary HHV-7 Infection in British children: antibody response and
detection of viral DNA.
Table 1
shows the results of HHV-6 and HHV-7 testing of samples from patients
10, 11, and 12. Patients 10 and 11 showed seroconversion to HHV-7 IgG
with low antibody avidity, and HHV-7 DNA was detected in saliva. HHV-7
DNA was also detected in the acute-phase serum of patient 10. In
patient 11, the antibody response had matured to high avidity 5 months
after seroconversion was first detected. There was no evidence of HHV-6
infection in either patient. In contrast, patient 12 showed rising
titers of both HHV-6 and HHV-7 IgG antibodies; the HHV-6 antibody was
of high titer and high avidity, whereas the HHV-7 antibody was of low
avidity initially but had matured to high avidity by 4 months. Both
HHV-6 and HHV-7 DNAs were detected in saliva; HHV-7 DNA was also
detected in the acute-phase plasma.
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Dual primary HHV-6 and HHV-7 infections in British children:
antibody response and detection of viral DNA.
Table
2 shows the results of HHV-6 and HHV-7
IgG antibody and avidity testing of samples from patients 13 and 14; in
each patient there was seroconversion to both viruses with low-avidity antibody. In patient 13, HHV-6 DNA was detected in cerebrospinal fluid,
and HHV-7 DNA was detected in saliva. In patient 14, both HHV-6 and
HHV-7 DNAs were detected in saliva and HHV-6 DNA was also detected in
cerebrospinal fluid and acute-phase serum.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Diagnosis of primary HHV-6 and/or HHV-7 infection by antibody responses is challenging since the two viruses share common antigenic epitopes (for reviews, see references 1 and 4) and there is limited cross-reactivity between naturally induced human antibodies against the two viruses (3). Primary HHV-6 infection may be easily diagnosed in an HHV-7-seronegative individual by comparing the titers of acute- and convalescent-phase sera and demonstrating HHV-6 antibody seroconversion and vice versa. However, difficulty occurs when there are rising titers of antibodies to both viruses (34). Such rises might be the result of dual primary infection, a dual rise in preexisting antibodies to each virus, or a primary infection with one virus that elicits a secondary antibody response to the other. In this paper we describe a solution to this problem by using indirect immunofluorescence tests for antibody avidity to differentiate the HHV-6 and HHV-7 antibody titers and avidity and, hence, primary and secondary responses.
In the first tests, HHV-6 and HHV-7 IgG antibody titers and avidities
were measured by immunofluorescence with a panel of children's sera
taken from birth up to age 3 years. The results (Fig. 1) confirm those
of earlier seroepidemiological investigations, which have shown that
HHV-6 infects almost all individuals at between 7 and 13 months of age,
most commonly at about 8 or 9 months (30, 36), whereas
HHV-7 infection occurs later (26, 37). As expected,
low-avidity antibodies were found only in the sera from the children
and not in the sera from the adults, and the age distribution in the
children with low-avidity antibodies agrees with that from a recent
study of the age at which primary HHV-6 and HHV-7 infections are found
(6). In most patients the low-avidity antibody was
detected for one virus only and the individual either was seronegative
or, more usually, had high-avidity antibody to the other virus, but in
a few patients, low-avidity antibody to one virus was accompanied by a
low level of antibody (titers, <40) of indeterminate avidity to the
other virus, suggesting limited cross-reactivity. In the remaining five
patients, dual low-avidity antibody (titers in all patients, 80) was
found, raising the possibility of an antigenic cross-reaction or
concurrent primary HHV-6 and HHV-7 infections. Overall, however, the
results supported the concept that HHV-6 low-avidity antibody occurs
only after primary HHV-6 infection and vice versa. Nevertheless, there was clearly a need to validate further the combined use of the two
antibody avidity tests with paired sera from patients with well-defined
primary HHV-6 and HHV-7 infections.
As regards the cases of serologically proven primary HHV-7 infection in Japanese children, in all three children a rising titer of low-avidity antibody to HHV-7 was accompanied by high-titer, high-avidity HHV-6 IgG antibody, and in agreement with others (25, 27), it was found that primary HHV-7 infection normally occurs after infection with HHV-6 and is accompanied by a secondary response to HHV-6. Turning to serologically proven primary HHV-6 infection in Japanese children, in all six children we documented seroconversion with low-avidity antibody to HHV-6, but in two children there were significant titers of antibody to HHV-7. In one child the rising titer of high-avidity antibody excluded primary HHV-7 infection. However, in the other child there was a rising antibody titer of low avidity to both viruses, suggesting dual primary infection, but the possibility of an antigenic cross-reaction could not be excluded.
Therefore, it remained necessary to further confirm the specificities of the two antibody avidity tests and to confirm that dual primary HHV-6 and HHV-7 infections can be distinguished. One way to do this would be by immunoblot antibody tests for specific HHV-6 and HHV-7 proteins known not to cross-react (2, 3). Another possibility is to confirm antibody specificity by testing for the presence of virus either by culture or by detection of viral DNA; such tests for HHV-6 or HHV-7 viremia have already been used in conjunction with antibody tests to confirm primary infection (6, 7). In the event, as viremia may be transient, we decided to test not only serum or plasma but also saliva and, where available, cerebrospinal fluid from the British children for HHV-6 and HHV-7 DNAs. The results (Table 2) show that when there was low-avidity antibody to both viruses, both HHV-6 and HHV-7 DNAs were detected, confirming dual primary HHV-6 and HHV-7 infections and excluding cross-reactivity. In addition, when there was serological evidence of primary HHV-7 infection but the child was seronegative for HHV-6, only HHV-7 DNA was detected, whereas when primary HHV-7 infection occurred after prior infection with HHV-6, both viruses were detected (Table 1).
In conclusion, the presence of viral DNA thus fits exactly with the antibody avidity findings and validates the use of the antibody avidity test to distinguish between primary HHV-6 and HHV-7 infections, despite the sharing of epitopes between these two closely related agents. Thus, future studies with HHV-6 and HHV-7 antibody avidity tests will be useful for the investigation of the clinical features of infection with these two closely related viruses.
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ACKNOWLEDGMENTS |
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We thank Shabnam Ansari for excellent technical assistance.
This work was supported in part by project grants to K.N.W. from Action Research (reference S/P/2459) and the Wellcome Trust (reference 051350/Z/97/Z).
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Virology, Royal Free and University College Medical School, Windeyer Building, 46 Cleveland St., London W1T 4JF, United Kingdom. Phone: 44 (0)20 7679 9490/9137. Fax: 44 (0)20 7580 5896. E-mail: k.n.ward{at}ucl.ac.uk.
Present address: Department of Infectious Diseases & Microbiology,
Imperial College School of Medicine, St. Mary's Campus, London W2 1PG,
United Kingdom.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Clinical Microbiology, March 2001, p. 959-963, Vol. 39, No. 3
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.3.959-963.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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