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Rheumatology 2002; 41: 833-834
© 2002 British Society for Rheumatology

Letters to the Editor

High mutation rate in the NS1 gene of parvovirus B19 DNA amplified from skeletal muscle of a case of mixed connective tissue disease

J. R. Kerr and W. M. H. Behan1

Department of Microbiology, Royal Brompton Hospital, Imperial College School of Medicine, Sydney Street, London SW3 6NP and
1 University Department of Pathology, Western Infirmary, Glasgow G-11 6NT, UK

SIR, Chevrel and colleagues report the presence of parvovirus B19 DNA in muscle of a patient with dermatomyositis [1]. In 1997, we reported the similar detection of parvovirus B19 DNA in skeletal muscle of a case of mixed connective tissue disease and arthralgia [2]. This was not cited probably because the publication was in a journal not abstracted by Medline. The case, however, has interesting parallels.

Our patient was a 39-yr-old female with a 6-month history of disease. She had a weakly positive ANA titre of 256, but tested negative for other autoantibodies, including rheumatoid factors La, Ro, SMA, RNP and Jo-1. The parvovirus B19 strain was sequenced between nucleotides 1399 and 1682, and revealed 10 mutations compared with the published sequence [3]; nucleotide (nt) 1443, C->T; nt 1455 C->T, nt 1466 G->C; nt 1476, A->G; nt 1482, C->T; nt 1491, C->T; nt 1506, C->T; nt 1554, A->G, nt 1602, C->A; nt 1611, C->A (GenBank accession no. 324452). This mutation rate of 3.52% compared with the wild type is much in excess of that expected (<1%) for highly conserved regions of the parvovirus genome [3–5]. All mutations were silent except that at nt 1466 (G->C), which had resulted in an amino acid change from serine to threonine at position 344 [2], immediately downstream of the Walker box A of the nucleoside triphosphate (NTP) binding site (amino acid positions 323–343) [6]. As cytotoxicity is closely associated with functional NTP binding, it may be that this mutation facilitated persistence by modifying cytotoxicity [8]. It is also important to note that threonine at position 344 is typical of adeno-associated virus type 2 (AAV-2) [3], which infects skeletal muscle, disrupting the troponin T gene, TNNT1, and integrating into human chromosome 19 (19q13.3-qter) at the AAVS1 locus [7]. In addition, we have reported the detection of parvovirus B19 DNA in the skeletal muscle of a case of chronic fatigue syndrome (CFS) [2]; nucleotide sequencing of the same region revealed two mutations compared with the published sequence, both of which were silent: nt 1530, A->G and 1638, A->C (GenBank accession no. 324453).

Cases of myositis as well as increases in serum muscle enzymes [8] have been associated with acute B19 infection. These include a child with juvenile dermatomyositis [9], another with B19-associated interstitial lung disease, hepatitis and myositis [10], a case of probable systemic lupus erythematosus associated with increased creatine kinase and aldolase [8] and a series of four cases from which B19 DNA was detected in skeletal muscle [11]. The case reported by Chevrel and colleagues [1] was positive for HLA-DR4, which has been associated with the development of and increased duration of arthritis following B19 infection [12, 13]. HLA-DR3 and DR4 are over-represented in cases of polymyositis [14, 15].

Parvovirus B19 exhibits a variety of virulence mechanisms which have relevance to the genesis of rheumatic disease and myositis [16], may result in chronic dysregulation of cytokines with raised circulating tumour necrosis factor-{alpha} (TNF-{alpha}) and interferon-{gamma} (IFN-{gamma}) [17], and may possibly integrate into peripheral blood leucocytes [18]. How it might achieve persistence and damage in skeletal muscle remains to be clarified.

Notes

Correspondence to: J. R. Kerr. Back

References

  1. Chevrel G, Calvet A, Belin V, Miossec P. Dermatomyositis associated with the presence of parvovirus B19 DNA in muscle. Rheumatology2000;39:1037–9.[Abstract/Free Full Text]
  2. Kerr JR, Barrett AM, Curran MD, Behan WMH, Middleton D, Behan PO. Parvovirus B19 and chronic fatigue syndrome. Chronic Fatigue Syndrome1997;3:101–7.
  3. Shade RO, Blundell MC, Cotmore SF, Tattersall P, Astell CR. Nucleotide sequence and genome organisation of human parvovirus B19 isolated from the serum of a child during aplastic crisis. J Virol1986;58:921–36.[Abstract/Free Full Text]
  4. Blundell MC, Beard C, Astell CR. In vitro identification of a B19 parvovirus promoter. Virology1987;57:534–8.
  5. Hokynar K, Brunstein J, Soderlund-Venermo M et al. Integrity and full coding sequence of B19 virus DNA persisting in human synovial tissue. J Gen Virol2000;81:1017–25.[Abstract/Free Full Text]
  6. Momoeda M Wong S, Kawase M, Young NS, Kajigaya S. A putative nucleoside triphosphate-binding domain in the nonstructural protein of B19 parvovirus is required for cytotoxicity. J Virol1994;68:8443–6.[Abstract/Free Full Text]
  7. Dutheil N, Shi F, Dupressoir T, Linden RM. Adeno-associated virus site-specifically integrates into a muscle-specific DNA region. Proc Natl Acad Sci USA2000;97:4862–6.[Abstract/Free Full Text]
  8. Kalish RA, Knopf AN, Gary GW, Canoso JJ. Lupus-like presentation of human parvovirus B19 infection. J Rheumatol1992;19:169–71.[Medline]
  9. Lewkonia RM, Horne D, Dawood MR. Juvenile dermatomyositis in a child infected with human parvovirus B19. Clin Infect Dis1995;21:430–2.[Medline]
  10. Bousvaros A, Sundel R, Thorne GM et al. Parvovirus B19-associated interstitial lung disease, hepatitis and myositis. Pediatr Pulmonol1998;26:365–9.[Web of Science][Medline]
  11. Crowson AN, Magro CM, Dawood MR. A causal role for parvovirus B19 infection in adult dermatomyositis and other autoimmune syndromes. J Cutan Pathol2000;27:505–15.[Web of Science][Medline]
  12. Klouda PT, Corbin SA, Bradley BA, Cohen BJ, Woolf AD. HLA and acute arthritis following human parvovirus infection. Tissue Antigens1986;28:318–9.[Medline]
  13. Gendi NST, Gibson K, Wordsworth BP. Effect of HLA type and hypocomplementaemia on the expression of parvovirus arthritis: one year follow up of an outbreak. Ann Rheum Dis1996;55:63–5.[Abstract/Free Full Text]
  14. Soriano ER, McHugh NJ. Overlap syndromes in adults and children. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, eds. Oxford textbook of rheumatology, edn 2. Oxford: Oxford University Press, 1999:1413–32.
  15. Targoff IN. Polymyositis and dermatomyositis. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, eds. Oxford textbook of rheumatology, edn 2. Oxford: Oxford University Press, 1999:1250–86.
  16. Kerr JR, Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis2000;59:672–83.[Free Full Text]
  17. Kerr JR, Barah F, Mattey DL et al. Serum tumour necrosis factor-{alpha} (TNF-{alpha}) and interferon-{gamma} (IFN-{gamma}) are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol2001;82:3011–9.[Abstract/Free Full Text]
  18. Reed JL, Kucukcetin B, Koenig S. Mechanisms of parvovirus B19 persistence in peripheral blood mononuclear cells. Infect Dis Rev2000;2:169.
Accepted 12 February 2002


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