Indian Journal of Human Genetics Medknow Publications on behalf of Indian Society of Human Genetics ISSN: 0971-6866 EISSN: 1998-362x Vol. 9, Num. 1, 2003, pp. 29-30

Indian Journal of Human Genetics, Vol. 9, No. 1, Jan-Jun, 2003, pp. 29-30

Special Report

Human herpesvirus 6: Catalyst of genomic lesion in dysfunctional hematopoiesis ?

Atanu Basu

National Institute of Virology (ICMR), 20A Dr. Ambedkar Road, Pune-411001.
Address for correspondence: Atanu Basu, National Institute of Virology (ICMR), 20A Dr Ambedkar Road, Pune-411001.

Code Number: hg03008

The Human herpesvirus type 6 (HHV6) originally discovered as a chance isolation from patients with human immunodeficiency virus infections, remain a virus whose disease causing potential remain incompletely understood.¹ Several major studies provided convincing evidence to link HHV6 with human illness. These included exanthum subitum, and possibly transient erythroblastopenia of childhood.² However, a rather large spectrum of undifferentiated illness ranging from febrile convulsions to fulminant hepatitis and possibly multiple scleoris, where suspected etiologic association of HHV6 has been proposed remain controversial.³

Interestingly, although most of the adult population shows evidence of antibodies against HHV6, the virus can reactivate and cause severe disease in immunocompromised hosts, specially transplant cases. The presentation can range from frank bone marrow failure to hepatitis and even encephalitis. However it is not clear what host and virus factors create and start this pathophysiologic event but the possible role of HHV6 in directly infecting human hematopoietic stem cells has been demonstrated.

Aplastic anemia is a form of bone marrow failure syndrome first described in 1888 by Paul Ehrlich. Although many aspects of the disease has been well studied over the years, several important etiologic considerations-specially the possible role of hematosuppressive viruses-remain incompletely understood.⁴ Herpesviruses have been indicated but no conclusive line of evidence has emerged to pinpoint their role in this disease. Case reports have shown possible infection with Epstein-Barr Virus (EBV) and perhaps CMV.⁵ In a subset of aplastic anemia cases, termed hepatitis associated aplastic anemia, a viral-hepatitis-like syndrome precedes the onset of aplastic anemia. No known hepatitis viruses have been isolated or demonstrated in such cases. The first possible role of HHV6 and CMV came from a recent study that showed a rather high prevalence of both human cytomegalovirus (CMV) and HHV6 DNA in the liver tissue of HAA cases, statistically significant when compared with appropriate controls. In all cases except one, the HHV6 was variant B but the CMV genotypes did not show predominance of a single subtype- suggesting a random reactivation pattern.⁶ Interestingly, cytokine profiling of such patients showed high prevalence of interferon g and pro-inflamatory cytokines like IL-10 (unpublished data) suggesting active infection process. The possible interaction of HHV6 with other herpesviruses like EBV in myelodysplastic and chronic myeloproliferative states had been further demonstrated where the viral antigen expression could be clearly shown in intrephine biopsy material taken from patients suggesting possible reactivation of these viruses as pathophysiologic factors in hematopoietic disorders.⁷ By itself, persistent bone marrow infection with HHV6 may also lead to chronic myelosupression.⁸

Interestingly in 1994, sequence analysis of the HHV6 genome revealed the presence of A(GGGTTA)n motifs identical to the human telomeric repeat sequence (TRS).⁹ These findings suggested that TRS elements may play important and yet incompletely understood role in the biology of HHV6 infection at a cellular level and perhaps more importantly interfere in some way with the host genome as was suggested from a recent study where latency associated nuclear antigens of HHV8 could transactivate telomerase reverse transcriptase promoters in Kaposi's sarcoma.¹⁰

In summary, the growing body of evidence for possible genome-interference role of HHV6 alone or in association with other herpesviruses, provides the beginning of our understanding towards an unique molecular pathophysiology of hematological diseases that in combination with environmental factors may constitute primary etiology of marrow failure syndromes. However, extensive studies are required to identify and differentiate such factors -both virus and host.

REFERENCES

1. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus: HBLV in patients with lymphoproliferative disorders. Science 1986;234:516
2. Yamanishi K, Okuno T, Shiraki K, et al. identification of human herpesvirus 6 as a causal agent of exanthum subitum. Lancet 1988;1:1065-7.
3. Wilborne F, Scmidt CA, Brinkman V, et al. A potential role of HHV6 in nervous system disease. J Neurovirol 1994;49:213.
4. Young NS. Bone marrow Failure Syndrome. WB Saunders Co; 2000. pp. 1.
5. Sullivan JL. Hematologic consequences of Epstein-Barr virus infection. Hematol Oncol Clin North Am 1987;1:397-417.
6. Basu A, Wong S, Neal S, Young KE. Brown (2001) No Association of Specific genotypes of CMV and HHV6 in hepatic Tissues of Patients with Hepatitis Associated Aplastic Anemia (HAA) Blood 2001;98:730.
7. Krueger GR, Kudlimay D, Ramon A, et al. Demonstration of active and latent Epstein-Barr virus and human herpesvirus-6 infections in bone marrow cells of patients with myelodysplasia and chronic myeloprolifertaive diseases. In vivo 1994;8:533-42.
8. Knox KK, Carrigan DR. Chronic myelosuppression associated with persistent bone marrow infection due to human herpesvirus 6 in a bone marrow transplant recipient. Clin Infect Dis 1996;22:174-5.
9. Thomson BJ, Dewhurst S, Gray D. Structure ad hetongeneity of the a sequences of human heresvirus 6 strain variants U1102 and Z 29 and identification of human telomeric repeat sequences at the genomie. Hermin J Virol 1994;68:307-14.
10. Knight JS, Cotter MA, Robertson ES. The latency-associated nuclear antigen of Kaposi's sarcoma associated herpesvirus transactivates the telomerase reverse transcriptase. J Biol Chem 2001;276:1-8.

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