Original Article
Latent Varicella–Zoster Viral DNA in Human Trigeminal and Thoracic Ganglia
N Engl J Med 1990; 323:627-631September 6, 1990
- Abstract
- Abstract
Background.
Some human herpesviruses become latent in dorsal-root ganglia. Primary infection with the Varicella Zoster virus causes chickenpox, followed by latency, and subsequent reactivation leading to shingles (zoster), but the frequency and distribution of latent virus have not been established.
Methods.
Using the polymerase chain reaction, we performed postmortem examinations of trigeminal and thoracic ganglia of 23 subjects 33 to 88 years old who had not recently had chickenpox or shingles to identify the presence of latent Varicella Zoster viral DNA. Oligonucleotide primers representing the origin of replication of the Varicella Zoster virus and Varicella Zoster virus gene 29 were used for amplification.
Results.
Among the 22 subjects seropositive for the antibody to the virus, both the viral origin-of-replication and gene-29 sequences were detected in 13 of 15 subjects (87 percent) in whom trigeminal ganglia were examined and in 9 of 17 (53 percent) in whom thoracic ganglia were examined. Viral DNA was not detected in brain or mononuclear cells from the seropositive subjects. None of three thoracic ganglia from the one seronegative subject contained Varicella Zoster viral DNA.
Conclusions.
These findings indicate that after primary infection with Varicella Zoster virus (varicella), the virus becomes latent in many ganglia — more often in the trigeminal ganglia than in any thoracic ganglion —and that more than one region of the viral genome is present during latency. (N Engl J Med 1990; 323: 627–31.)
Article Activity
- Article
ALL human herpesviruses establish latent infection. The human herpesviruses — in particular, Epstein–Barr virus, herpes simplex virus, and varicella–zoster virus — have served as models for the study of latency. Varicella–zoster virus causes chickenpox (varicella) in children, becomes latent in dorsal-root ganglia, and is reactivated decades later, causing shingles (zoster) in adults. During latency, viral DNA is maintained in infected cells and virions cannot be detected, although virus can often be recovered by explantation of latently infected tissues. The mechanisms of latency and reactivation are not known. That they probably differ among the various herpesviruses is suggested by the establishment of latent cytomegalovirus and Epstein–Barr virus in extraneural sites, in contrast to the localization of herpes simplex virus types 1 and 2 and varicella–zoster virus in dorsal-root ganglia. Moreover, explantation of latently infected tissues leads to the reactivation of herpes simplex virus type 1 from trigeminal and other cranial-nerve ganglia1 2 3 and herpes simplex virus type 2 from sacral ganglia.4 Attempts to recover varicella–zoster virus from human thoracic ganglia have failed, however.5
We previously reported the detection of latent viral DNA in human trigeminal ganglia by means of Southern blot hybridization.6 The extension of methods of nucleic acid hybridization has begun to yield information on the expression of varicella–zoster viral DNA in ganglia.6 7 8 9 In particular, the polymerase chain reaction has provided the means to examine a virus at the molecular level with a specificity and precision not previously possible. In addition, the polymerase chain reaction permits the sample size of the study to be increased, because it allows simultaneous and efficient analyses of multiple samples. Furthermore, only a small fraction of a single ganglion is needed for the polymerase chain reaction, and the remainder is available for other analyses. Finally, only a short exposure time after hybridization is required. We have used the polymerase chain reaction to confirm the presence of latent varicella–zoster viral DNA in human ganglia and to provide new information on the distribution of the virus in multiple levels of the human neuraxis.
Methods
Tissue Specimens
Trigeminal and thoracic ganglia and blood were obtained from 23 adult subjects 2 to 24 hours after death. A brain-tissue specimen was obtained from the pons of a 31-year-old man who died of a gunshot wound (who was not in the study group of 23 subjects). A liver-tissue specimen was obtained from a one-day-old infant. The clinical diseases observed in the 23 subjects are shown in Table 1Table 1
Results of Polymerase-Chain-Reaction Analysis of DNA from Human Ganglia.*. None had a history of recent varicella or zoster or had skin lesions consistent with recent infection with varicella–zoster virus. The ganglia were removed aseptically, washed twice in Dulbecco's modified Eagle's medium (Grand Island Biological Co., Grand Island, N.Y.), and stored at —70°C. They were examined individually or pooled. As controls, ganglia from a newborn who died two hours after birth and blood from a healthy 38-year-old woman seropositive for varicella–zoster virus antibody were used in the isolation of DNA.DNA Isolation
Ganglia were thawed and Dounce-homogenized in 2 ml of 0.010 M TRIS–hydrochloric acid (pH 7.5), 0.1 M sodium chloride, and 0.050 M EDTA buffer (TNE buffer) per 0.5 cm3 of tissue at 4°C, and digested with sodium dodecyl sulfate (final concentration, 0.5 percent) and proteinase K (200 μg per milliliter) for one hour at 37°C or overnight at room temperature. DNA was extracted three times with phenol, twice with phenol:chloroform (1:1), and three times with chloroform and then precipitated with ethanol; the extracted DNA was redissolved in 0.010 M TRIS–hydrochloric acid (pH 8.0) and 0.001 M EDTA buffer (TE buffer) (100 μl per 0.5 cm3 of tissue). The concentration of DNA was estimated by recording the optical density at 260 nm, and the final concentration of DNA was adjusted to 1 μg per microliter. DNA was also extracted from human mononuclear cells as previously described.10
Cells, Viruses, and Antibodies
The propagation of varicella–zoster virus and herpes simplex virus type 1 in African green monkey (BSC-1) cells and the extraction of DNA have been described elsewhere.10 , 11 The presence of the antibody to varicella–zoster virus in human serum was determined by immunoprecipitation.12
Polymerase Chain Reaction
Oligonucleotide primers were chosen from published sequences of varicella–zoster virus and globin DNA13 , 14 and obtained from Research Genetics (Huntsville, Ala.). Origin-of-replication primer a (5′-GTGGGGGGGTGAAAAAGGGGGGGG-3′) is located between nucleotides 110,033 and 110,057 on the varicella–zoster virus genome, origin-of-replication primer b (5′-TCACGTCAAATCGATTTTAAAAAG-3′) is located between nucleotides 110,336 and 110,360, and origin-of-replication internal oligonucleotide c (5′-ATGTCTGTGGTGTACGCCAATCGG-3′) is located between nucleotides 110,076 and 110,100. Gene 29 encodes the major DNA binding protein. Gene-29 primer 1 (5′-TACGGGTCTTGCCGGAGCTGGTAT-3′) is located between nucleotides 50,839 and 51,089, gene-29 primer 2 (5′-AATGCCGTGACCACCAAGTATAAT-3′) is located between nucleotides 51,314 and 51,338, and gene-29 internal oligonucleotide 3 (5′-ACTCACTACCAGTACTTTCT-3′) is located between nucleotides 51,098 and 51,118 (Fig. 1Figure 1
Location of Regions within the Varicella–Zoster Virus Genome Used for Detection with Polymerase Chain Reaction. ). Stock solutions containing 1 μg of the oligonucleotide per microliter of sterile water were diluted to produce 20 μM aliquots for use in the polymerase chain reaction.The polymerase chain reaction was performed with a commercially available kit (Gene Amp Kit, Perkin–Elmer–Cetus, Emeryville, Calif.). In a typical reaction, 1 μg of tissue DNA or 1 ng of uninfected or virus–infected cell DNA or an equivalent volume of sterile water was used as a template in a final 100-μl reaction mixture containing 0.010 M TRIS–hydrochloric acid (pH 8.3), 0.050 M potassium chloride, 0.015 M magnesium chloride, and 0.01 percent gelatin and deoxyadenosine triphosphate, deoxythymidine triphosphate, deoxycytidine triphosphate, and deoxyguanosine triphosphate (each nucleotide at a final concentration of 200 μM), 1 μmol of each primer, and 2.5 units of Thermus aqualicus DNA polymerase (Taq). Samples were heated to 95°C for five minutes before Taq DNA polymerase was added.
An automated DNA thermal cycler (Perkin–Elmer–Cetus) was set for a denaturation step of 2 minutes at 94°C, an annealing step of 2 minutes at 45°C, and an elongation step of 3 minutes at 72°C that was automatically extended by 15 seconds per cycle. The total number of cycles was 50. In experiments that included beta-globin primers, the conditions were those described above except that the denaturation step was set for one minute at 95°C, the annealing step was set for two minutes at 60°C, and the number of cycles was 35.
Virus–Specific Sequences in Amplified Products
Synthetic oligonucleotides representing a region internal to the amplified fragment were dissolved in sterile water to a final concentration of 0.1 μg per microliter, and an aliquot (20 μl) was used for end labeling with [gamma-32P]adenosine triphosphate (ICN, Costa Mesa, Calif.; 7000 Ci per millimole) as previously described.17
The specificity of the amplified sequence was determined by Southern blot hybridization. One microliter of a total volume of 100 μl of the polymerase-chain-reaction mixture containing varicella–zoster virus–infected cell DNA and 12 μl from the other mixtures were used for analysis. Amplified DNA fragments were separated by electrophoresis on a 2 percent agarose gel in a solution of 0.04 M TRIS—acetic acid and 0.002 M EDTA buffer (pH 8.0). DNA fragments in the agarose gel were transferred to a Zeta-probe membrane (Bio-Rad, Richmond, Calif.), hybridized to 32Pend-labeled oligonucleotide probes, and identified by autoradiography performed according to the manufacturer's instructions. The size of the amplified product was determined by comparing it against standard molecular-weight markers (a 123-bp [base pair] ladder, from Bethesda Research Laboratories, Gaithersburg, Md.).
Results
oligonucleotide primers representing the varicella–zoster virus origin of replication and gene 29 were chosen from the published nucleotide sequence of the viral genome13 (Fig. 1). Initially, DNA was extracted from trigeminal and thoracic ganglia that had been obtained from 2 adults (not in the study group of 23 subjects), pooled, and analyzed by polymerase chain reaction for the varicella–zoster virus origin of replication. Amplification of a 325-bp DNA fragment located along the varicella–zoster virus origin of replication indicated the presence of viral DNA in infected tissue-culture cells and ganglia latently infected by the virus; no varicella–zoster virus origin-of-replication sequences were detected on polymerase-chain-reaction testing of DNA from trigeminal or thoracic ganglia of the newborn, testing of DNA from human brain or liver tissue, mononuclear cells, BSC-1 cells infected with herpes simplex virus, or uninfected BSC-1 cells, or testing without DNA (Fig. 2Figure 2
Detection of Varicella–Zoster Viral DNA in Human Ganglia by Polymerase Chain Reaction.).Co-amplification of a cellular gene (beta-globin)14 and varicella–zoster virus origin-of-replication sequences was performed to show that each DNA sample contained an amplifiable gene and that the amplification of sequences of the virus from human ganglia was specific. An analysis of duplicate samples with the use of internal oligonucleotide probes specific for human beta-globin and the varicella–zoster virus origin of replication revealed viral sequences (325 bp) only in ganglia from two adults, whereas beta-globin sequences (110 bp) were detected in DNA samples from all human tissues (Fig. 3Figure 3
Co-amplification of Human Beta-Globin—Specific and Varicella–Zoster Virus–Specific Sequences from DNA Extracts of Human Tissue.). Furthermore, the human beta-globin primers did not yield amplification products from either uninfected or varicella–zoster virus–infected monkey kidney (BSC-1) cells, indicating a lack of homology between human and monkey beta-globin genes with respect to the primed segment.After DNA from pooled ganglia of two adults was shown to contain the varicella–zoster virus origin of replication by means of the polymerase chain reaction, DNA from each of two trigeminal ganglia and pooled DNA from two thoracic ganglia of another person (Subject 1 [Table 1]) were analyzed for the presence of varicella–zoster virus gene 29 in addition to the varicella–zoster virus origin of replication. Sequences representing both these varicella–zoster virus genes were detected in DNA samples from Subject 1 (Fig. 4Figure 4
Detection of Varicella–Zoster Viral DNA in Human Ganglia by Polymerase Chain Reaction with Primers Representing Different Regions of the Varicella–Zoster Virus Genome.).After the presence of both varicella–zoster virus origin of replication and gene 29 in human ganglia was confirmed, the prevalence and distribution of latent varicella–zoster virus were prospectively analyzed by examining DNA samples extracted from 24 trigeminal and 61 thoracic ganglia of the 23 study subjects (Table 1). The DNA from all ganglia was analyzed in triplicate. Twenty-two subjects were seropositive and one was seronegative for varicella–zoster virus on immunoprecipitation. An analysis of 24 individual trigeminal ganglia from 15 seropositive subjects revealed the presence of varicella–zoster viral DNA in 20 ganglia (83 percent) from 13 subjects (87 percent). Thoracic ganglia from 18 seropositive subjects and 1 seronegative subject were either pooled (those of 12 subjects) or examined individually (those of 6 subjects). When pooled ganglia were examined, varicella–zoster viral DNA was found in the ganglia of seven subjects; when the individual ganglia were examined, viral DNA was found in 6 of 16 ganglia (38 percent) from three of the six subjects (50 percent). None of three thoracic ganglia from the one seronegative subject (Subject 17) contained varicella–zoster viral DNA. Three thoracic ganglia from one subject (Subject 20) were positive for varicella–zoster virus origin of replication but negative for gene 29.
Of 11 subjects in whom both trigeminal and thoracic ganglia were studied, 8 (73 percent) had detectable latent varicella–zoster viral DNA in ganglia from both levels of the neuraxis. In one (Subject 22), viral DNA was found only in trigeminal ganglia. None of the subjects had detectable latent varicella–zoster viral DNA exclusively in thoracic ganglia, and two seropositive subjects did not have detectable viral DNA in either trigeminal or thoracic ganglia. There was no difference between the trigeminal ganglia of the left side and those of the right. In all, 14 of 22 seropositive subjects (63 percent) were found to have varicella–zoster viral DNA in one or more ganglia (Table 1).
Finally, the DNA from two trigeminal ganglia and pooled thoracic ganglia of Subject 1 that were positive for varicella–zoster virus origin of replication and gene 29 (Fig. 4) was also analyzed for two more varicella–zoster virus sequences (genes 40 and 28). These three DNA samples were found to contain the additional sequences (data not shown).
Discussion
Latent varicella–zoster viral DNA in human ganglia was detected by polymerase chain reaction. Among 22 seropositive subjects, both the varicella–zoster virus origin of replication and gene 29 were detected in trigeminal ganglia from 13 of 15 subjects (87 percent) and in thoracic ganglia from 9 of 17 subjects (53 percent). None of three thoracic ganglia from one seronegative subject contained varicella–zoster viral DNA. The absence of the same virus–specific sequences in ganglia and liver tissue from a newborn and in brain and mononuclear cells from seropositive persons supports the prediction of earlier epidemiologic studies that in humans with primary infection, varicella–zoster virus becomes latent exclusively in dorsal-root ganglia.18 Our results show that the virus becomes latent in multiple ganglia, more often in individual trigeminal ganglia than in any individual thoracic ganglion, and that more than one region of the varicella–zoster virus genome is present during latency. These observations confirm and extend the previous finding of latent varicella–zoster viral DNA in human trigeminal ganglia on Southern blot hybridization.6
Polymerase chain reaction permitted simultaneous analysis of multiple ganglia from different subjects. Our findings are consistent with those of the clinical and pathological studies of Head and Campbell19 and Hope-Simpson,18 which showed not only that the face (supplied by afferent nerves from the trigeminal ganglion) is affected more by zoster than any other single dermatome, but also that multiple ganglia may be infected by varicella–zoster virus. Although varicella–zoster virus sequences were detected more frequently in randomly sampled trigeminal ganglia than in thoracic ganglia, these sequences were nevertheless present in the thoracic ganglia of more than half the subjects examined. Since there are 12 pairs of thoracic ganglia and only 1 pair of trigeminal ganglia, analysis of all 24 thoracic ganglia from each subject might have identified more subjects whose thoracic ganglia contained latent varicella–zoster viral DNA.
No varicella–zoster virus sequences were detected in three thoracic ganglia from the only subject who was seronegative for the virus (Subject 17) or in ganglia from a newborn (Fig. 1 and 2). The failure to detect varicella–zoster viral DNA in seronegative persons most likely reflects an absence of primary infection with the virus. An inability to amplify latent varicella–zoster viral DNA is a possible explanation but seems unlikely, since a cellular gene (beta-globin) was successfully amplified in DNA from every human tissue analyzed. The absence of detectable varicella–zoster viral DNA in both trigeminal and randomly sampled thoracic ganglia from two seropositive subjects (Subjects 14 and 15) may reflect limited sampling of their ganglia.
It is noteworthy that varicella–zoster virus sequences from various regions of the viral genome were detected in the latently infected ganglia. In our study, all ganglia were analyzed for the presence of both varicella–zoster virus origin-of-replication and gene-29 sequences; both sequences were found in 14 of the 15 subjects in whom the virus was detected (Table 1). Since the varicella–zoster virus origin of replication is about 60 kb downstream from gene 29, the data show that more than one region of the viral genome is present in latently infected human ganglia. In one instance, we attempted to detect two additional varicella–zoster virus sequences in multiple ganglia from one subject. We found varicella–zoster virus sequences representing genes 28 and 40 (in addition to varicella–zoster virus origin of replication and gene 29), suggesting that much of the genome of the virus is present during latency. This finding might have been predicted, since varicella–zoster viral DNA6 and RNA8 , 9) representing different portions of the genome have been detected in latently infected ganglia.
Supported in part by Public Health Service grants (AG-06127, AG-07347, and NS-07321) from the National Institutes of Health, a pilot grant from the National Multiple Sclerosis Society, and a grant from the Beatrice and Roy Backus Foundation.
We are indebted to the Departments of Pathology at University Hospital, the Veterans Affairs Hospital, Denver General Hospital, the Presbyterian–St. Luke's Medical Center, the Children's Hospital, and the Fitzsimmons Army Medical Center in Denver for allowing us access to autopsy material; to Dr. Gary Zerbe, Dr. Gary Cabirac, and David Young for helpful suggestions; to Mary Devlin for technical assistance; to Marina Hoffman for editorial review; and to Marcia Conner for assistance in the preparation of the manuscript.
Source Information
From the Departments of Neurology (R.M., M.W., W.W., A.N.D., R.C., A.V., D.G.) and Microbiology and Immunology (A.V., D.G.), University of Colorado Health Sciences Center, Denver. Address reprint requests to Dr. Mahalingam at the Department of Neurology, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262.
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