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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1545-1549
Inheritance of Chromosomally Integrated Human Herpesvirus 6 DNA
By
Masanori Daibata,
Takahiro Taguchi,
Yuiko Nemoto,
Hirokuni Taguchi, and
Isao Miyoshi
From the Departments of Medicine and Anatomy, Kochi Medical School,
Kochi, Japan.
 |
ABSTRACT |
Human herpesvirus 6 (HHV-6) genome has been detected in several
human lymphoproliferative disorders with no signs of active viral
infection, and found to be integrated into chromosomes in some cases.
We previously reported a woman with HHV-6-infected Burkitt's
lymphoma. Fluorescence in situ hybridization showed that the viral
genome was integrated into the long arm of chromosome 22 (22q13). The
patient's asymptomatic husband also carried HHV-6 DNA integrated at
chromosome locus 1q44. To assess the possibility of chromosomal
transmission of HHV-6 DNA, we looked for HHV-6 DNA in the peripheral
blood of their daughter. She had HHV-6 DNA on both chromosomes 22q13
and 1q44, identical to the site of viral integration of her mother and
father, respectively. The findings suggested that her viral genomes
were inherited chromosomally from both parents. The 3 family members
were all seropositive for HHV-6, but showed no serological signs of
active infection. To confirm the presence of HHV-6 DNA sequences, we
performed polymerase chain reaction (PCR) with 7 distinct primer pairs
that target different regions of HHV-6. The viral sequences were
consistently detected by single-step PCR in all 3 family members. We
propose a novel latent form for HHV-6, in which integrated viral genome can be chromosomally transmitted. The possible role of the
chromosomally integrated HHV-6 in the pathogenesis of
lymphoproliferative diseases remains to be explained.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
SINCE THE FIRST isolation of human
herpesvirus 6 (HHV-6),1 it has become apparent that
infection by this virus is widespread. As with other herpesviruses,
HHV-6 remains latent in the host after primary infection.2
Transmission of HHV-6 via saliva from mother to infant is thought to be
the most common route.2 Besides being an infectious agent,
HHV-6 has been cited as a possible etiological factor or as a
modulating element of certain human neoplastic diseases, particularly
lymphoproliferative disorders. HHV-6 genome was detected in Hodgkin's
disease, various types of non-Hodgkin's lymphomas, and acute
lymphoblastic leukemia (ALL),3-10 but the question of how
HHV-6 exists in these neoplastic cells has not yet been fully answered.
We recently showed the integration of HHV-6 in the leukemic blast cells
of a patient with ALL4 and proposed that the chromosomally
integrated HHV-6 could be transmitted from generation to
generation.11 Supportive evidence for this novel mode of
viral transmission has been desired.
We previously reported a case of HHV-6 genome-positive Burkitt's
lymphoma,3 in which the viral genome was found to be
integrated into the long arm of chromosome 22 (22q13) of the lymphoma
cells.12 This case provided a unique opportunity to
investigate chromosomal transmission of HHV-6 in the patient's family.
| |
MATERIALS AND METHODS |
Fluorescence in situ hybridization (FISH) on metaphase chromosomes.
Metaphase chromosome preparations were obtained from leukemic
peripheral blood from the patient with HHV-6+ Burkitt's
lymphoma3 and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from the patient's family
members and 3 HHV-6-seropositive healthy donors. The cells were
synchronized by treatment with 5-bromodeoxyuridine for 16 hours, and
thereafter the cells were released from the block by incubation in
fresh medium containing thymidine for 6 hours as previously
described.13 Metaphase cells and chromosome spreads were
obtained according to standard procedures. Probe containing a
BamHI fragment (6.9 kb) of HHV-6, which was cloned DNA inserted into a plasmid (pH6Z-101) (supplied by Dr P.E. Pellett, Centers for
Disease Control and Prevention, Atlanta, GA),14 was labeled with biotinylated 14-deoxyadenosine triphosphate (14-dATP)
by nick translation. This probe proved to be specific for HHV-6. Forty
microliters of hybridization solution (hybrisol VII; Oncor, Gaithersberg, MD) containing 50 ng of the biotinylated probe was denatured at 70°C for 2 minutes and applied to RNase-treated
chromosome preparations, which were then incubated at 37°C overnight
in a humidified chamber. The slides were washed twice for 10 minutes in
50% formamide in 2× standard saline citrate (SSC) (0.3 mol/L sodium
chloride, 30 mmol/L sodium citrate, pH 7.0) at 43°C, followed by two
rinses in 2 × SSC at 37°C. The hybridized probe was detected by
incubation with fluorescein isothiocyanate-conjugated avidin. The
chromosomes were counterstained with propidium iodide and diamidino-2-phenylindole (DAPI). The slides were observed with a BX50
epifluorescence microscope (Olympus, Tokyo, Japan) and microphotographs
were taken on Provia Fujichrome 100 film (Fuji Film, Tokyo, Japan).
Primers and polymerase chain reaction (PCR).
For HHV-6 DNA amplification by PCR, 7 sets of primers from different
regions of the HHV-6 genome were used (Table
1). DNA was obtained using the phenol
chloroform-extraction technique after proteinase K digestion. A total
of 0.1 µg of genomic DNA was amplified in 50 µL of PCR buffer (10 mmol/L Tris-HCl, pH 8.3, 50 mmol/L KCl, 1.5 mmol/L MgCl2)
with 0.2 mmol/L of each deoxynucleoside triphosphate, 1.5 U Taq
polymerase enzyme (Takara Shuzo, Shiga, Japan), and 0.2 µmol/L of
each pair of primers. Reaction mixtures were incubated at 94°C for 3 minutes for denaturation followed by 25 cycles at 94°C for 1 minute,
57°C for 1 minute, and 72°C for 1 minute. A terminal extension at
72°C for 5 minutes was performed after completion of the 25 cycles. A
total of 20% of the amplification products (10 µL) was
electrophoresed on a 2% agarose gel followed by ethidium bromide
staining and visualization under ultraviolet light for the presence of
DNA bands of appropriate sizes.
| |
RESULTS |
The patient was a 58-year-old Japanese woman with Burkitt's lymphoma.
Her blood samples were positive for HHV-6 DNA by PCR.3 By
using the HHV-6+ lymphoma cell line established from the
patient, we showed integration of HHV-6 at chromosome locus 22q13 in
the lymphoma cells.12 The presence of HHV-6 DNA was also
shown by Southern blot hybridization using the BamHI fragment
of HHV-6 as probe.3,12 In this study, FISH with the
HHV-6-specific pH6Z-101 probe was also performed on metaphase
chromosomes from the peripheral blood in a leukemic phase. FISH allows
the identification of integrated viral genome as well as episomal viral
genome, because episomes should be associated with chromosomes
randomly, whereas integrated copies should give rise to symmetrical
hybridization signals at distinct chromosomal sites.15,16
FISH enabled us to directly visualize the integrated HHV-6 DNA at the
single-cell level. Specific symmetrical doublet signals on both
chromatids of a single homolog of chromosome 22 were observed in
approximately 70% of the peripheral blood metaphase cells examined
(Fig 1A). Q-banding-like DAPI staining
indicated that the signals on chromosome 22 were located at q13. The
finding confirmed that the patient carried integrated HHV-6 DNA on
chromosome 22q13.
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| Fig 1.
FISH on metaphase chromosomes from the lymphoma patient
(A), patient's husband (B), and their daughter (C). Hybridization with
an HHV-6-specific probe showed HHV-6 integration with symmetrical
doublet signals at homologous sites of both chromatids. Arrow and arrow
head indicate the hybridization signals on chromosome loci 1q44 and
22q13, respectively. Chromosomes were counterstained with propidium
iodide.
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|
We next examined the patient's family members for the presence of
HHV-6 genome. After obtaining informed consent, we obtained peripheral
blood from her asymptomatic 68-year-old husband. PBMCs were incubated
with PHA for 3 days and subjected to FISH analysis. Unexpectedly,
symmetrical doublet hybridization signals were seen on chromosome 1q44
in about 60% of metaphase cells (Fig 2A)
and, therefore, he was also thought to carry the HHV-6 genome
integrated on chromosome 1q44. To assess chromosomal transmission of
HHV-6 DNA, we looked for the viral genome in their healthy 35-year-old daughter. HHV-6 DNA was detected on both chromosome loci 22q13 and 1q44
in about 90% of PHA-stimulated PBMCs (Fig 1C), identical to the site
of viral integration of her mother and father, respectively. The
results strongly suggested that her viral genomes were inherited chromosomally from both parents. The 3 family members were all seropositive for HHV-6, but showed no serological signs of active infection (anti-HHV-6 immunoglobin G (IgG), 1: 160; anti-HHV-6 IgM,
<1:10). In parallel experiments, PHA-stimulated PBMCs from 3 control
HHV-6-seropositive healthy adults did not show any signals after
hybridization.
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| Fig 2.
Detection of HHV-6 DNA by PCR with 7 distinct primer
pairs that target different regions of the HHV-6 genome. The PCR
products were subjected to electrophoresis and stained with ethidium
bromide. The products were all of the predicted sizes. (A) HHV-6 U4
gene. (B) U31 gene. (C) U57 gene. (D) U67 gene. (E) U89 gene. (F) U94
gene. (G) HHV-6 sequence located between U91 and U92 genes. Lane 1, patient; lane 2, patient's husband; lane 3, their daughter; lane 4, healthy adult donor as a negative control; lane 5, HHV-6B-infected
cord blood cells as a positive control; lane M,
 X174/HincII-cut DNA size marker.
|
|
To confirm the presence of HHV-6 DNA sequences, we performed extensive
PCR analysis with 7 distinct primer pairs that target different regions
of HHV-6, including U4, U31, U57, U67, U89, U94 genes, and a sequence
located between U91 and U92 genes. These HHV-6 DNA sequences are
located away from the sequences that hybridize with the pH6Z-101
probe.17 The viral sequences were consistently detected by
single-step PCR in all 3 family members (Fig 2), suggesting high copy
numbers of HHV-6 genome. Under the same PCR conditions, no HHV-6 DNA
sequences were detected in PBMCs of our control HHV-6-seropositive adults.
Furthermore, attempts were made to establish lymphoblastoid cell lines
from the PBMCs of the patient's husband and daughter. Epstein-Barr
virus (EBV) and Herpesvirus saimiri (HVS) selectively infect B and T
cells, respectively, and immortalize them to give rise to continuously
growing cell lines.18-21 By exploiting this viral
transforming capacity, we have successfully established 2 HHV-6-carrying B- and T-cell lines from each of them. The presence of
HHV-6 DNA in these cell lines was confirmed by PCR with 7 sets of
primers as described above as well as Southern blot hybridization with
the pH6Z-101 probe (data not shown). The EBV-immortalized cell lines
possessed the activated B-cell phenotype, whereas the HVS-immortalized
cell lines were CD8+ T-cell lines. Both B- and T-cell lines
from the patient's husband carried integrated HHV-6 DNA at chromosome
1q44, while both B- and T-cell lines derived from the daughter had the
viral genome integrated at both chromosomes 22q13 and 1q44 (data not shown).
| |
DISCUSSION |
In this study, we detected the integrated HHV-6 genome at chromosome
locus 22q13 in a patient with Burkitt's lymphoma and at 1q44 in the
patient's husband. Moreover, we showed that their daughter carried the
HHV-6 genome at both 22q13 and 1q44, which are the identical sites of
HHV-6 integration of her mother and father, respectively. We also
reported a latent form of HHV-6 in an ALL family, in which
chromosomally integrated viral genome at 1q44 was shown to be
transmitted serially in 3 generations.11 These observations
provide convincing evidence for chromosomal transmission of the HHV-6
genome, which is a phenomenon to be known for the first time for the
Herpesviridae. HHV-6 is the causative agent of exanthem subitum in
early childhood,22 and most adults are thought to be
latently infected with this virus. However, such HHV-6 latency in
adults is usually characterized by a very low copy number of HHV-6
genome in peripheral blood, detectable only by highly sensitive
nested-PCR.23 In this respect, chromosomally integrated
HHV-6 with a high copy number of HHV-6 genome should be distinct from
the latency after primary infection. Indeed, HHV-6 DNA sequences in our
3 family members were detectable by single-step PCR with only 25-cycle
amplification using 0.1 µg genomic DNA as template, whereas in our
parallel experiments neither FISH nor PCR detected HHV-6 DNA in
peripheral blood of 3 control HHV-6-seropositive adults.
It may be argued that we are detecting a cellular gene with homology to
a viral gene in the family members. However, this would be unlikely,
because HHV-6 DNA sequences were consistently detected by Southern blot
hybridization as well as PCR with 7 primer pairs from different regions
of HHV-6 including U4, U31, U57, U67, U89, U94 genes, and a sequence
located between U91 and U92 genes. It also excludes the possibility
that only a small fragment of HHV-6 is integrated, but further analysis
is needed to clarify whether the integrated viral genome is complete.
Our FISH analysis showed that not all metaphase cells were positive for
hybridization signals. This may appear to be contradictory to our
proposal of chromosomal transmission of HHV-6 DNA because HHV-6 should
be present in all cells if it is constitutionally integrated. However,
signal-negative cells may have been false-negative for HHV-6 DNA
because of technical difficulty of FISH, and the hybridization
efficiency would be increased if longer HHV-6 DNA fragments are used as probes.
Although the most common mode of infection with HHV-6 is by salivary
transmission, several studies suggested that intrauterine or perinatal
transmission may occur. Aubin et al24 reported that 1 of 52 aborted fetuses was positive for HHV-6 DNA by PCR in PBMCs, thymus,
liver, spleen, brain, and cerebrospinal fluid. HHV-6 DNA sequences were
also found in PBMCs of the mother, but no HHV-6-specific IgM antibody
was detected in maternal serum and fetal plasma. Adams et
al25 showed that HHV-6 DNA was detected in 5 of 305 cord
blood samples, but HHV-6 IgM antibody could not be found in the fetal
sera of the HHV-6 DNA+ cases. Although these findings were
interpreted as indicative of intrauterine infection, the possibility of
chromosomal transmission of HHV-6 from parents to offspring should be
explored. To survey the prevalence of carriers of chromosomally
integrated HHV-6 in a population from our geographic area, we also
investigated the presence of HHV-6 DNA in cord blood samples. HHV-6 DNA
could not be found in any of our 58 cord blood specimens.26
The incidence of chromosomal transmission of HHV-6 genome appears to be
rare, but the present findings should alert investigators to the
presence of HHV-6 as an inheritable chromosomal element. Of 3 family
members carrying the integrated HHV-6 DNA in this study, 2 remain
healthy. Further investigations are needed to clarify its role in the
pathogenesis of lymphoproliferative diseases.
| |
ACKNOWLEDGMENT |
We thank P.E. Pellett for the gift of HHV-6-specific DNA probe,
pH6Z-101. We are also grateful to M. Yasukawa for providing HVS.
| |
FOOTNOTES |
Submitted January 12, 1999; accepted May 4, 1999.
Supported by a grant-in-aid for scientific research from the Japanese
Ministry of Education, Science and Culture (to M.D.).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Masanori Daibata, MD, Department of
Medicine, Kochi Medical School, Kochi 783-8505, Japan.
| |
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TOP
ABSTRACT
INTRODUCTION