in the progression of HIV infection to AIDS? (iii) Is ... as exanthem subitum, or sixth disease, consists of a ... human herpesvirus-6 as a causal agent for exanthem.
J. Med. Microbiol. -Vol. 36 (1992), 221-222
01992 The Pathological Society of Great Britain and Ireland
E D IT0R IAL
Human herpesvirus-6 This novel human herpesvirus was first isolated in 1986 after the observation of a cytopathic effect (CPE) in long-term cultures of peripheral blood mononuclear cells from six patients with lymphoproliferative disorders; electronmicroscopy revealed herpesvirus particles. The virus was shown to be serologically and genomically distinct from other human and several animal herpesviruses,by use of monoclonal antibodies and polyclonal antisera, and by cross-hybridisation studies. Several closely related isolates were later reported from Europe, Japan, Australia, South Africa and the USA. The virus was originally thought to replicate only in B lymphocytes, and was known as human B cell lymphotropic virus, but its cellular tropism in vitro is diverse, and the virus is more properly referred to as human herpesvirus type-6 (HHV6). HHV6 has a double-stranded DNA genome of about 170 kb. Sequencingstudies indicate that, among the human herpesviruses, HHV6 is most similar to cytomegalovirus (CMV), some regions of which crosshybridise under stringent conditions. Such genomic relationships suggest that HHV6 should be classified as a P-herpesvirus, rather than as a lymphotropic or yherpesvirus.2 The similarity with CMV is further emphasised by the response of HHV6 to antiviral agents : viral growth in vitro is sensitive to ganciclovir and foscarnet, but relatively resistant to acyclovir. Variations in the replicative and antigenic properties among strains of HHV6 have been demonstrated, as have restriction fragment length polymorphisms, but the significance of this heterogeneity is not known. HHV6 can be isolated from the saliva of seropositive individuals, and this is the likely route of transmission of the virus.3 Replicating virus has also been demonstrated in submandibular salivary gland biopsies by in-situ hybridisation and immunohistochemical~ t a i n i n gHowever, .~ the site of latency of the virus has not been identified with certainty. Viral DNA has been detected in adherent mononuclear cells from healthy adults,’ and virus can be recovered from CD4- and CD8-positive T cells during acute infection. HHV6 has also been isolated from a kidney biopsy specimen.ti Several age-related serosurveys have demonstrated that 60-90% of adults (depending on the assay conditions used) are infected with HHV6, and that infection is usually acquired in infancy.’ Clinically, the current areas of interest in HHV6 may be summarised as: (i) Does HHV6 infection result in serious disease? (ii) Does HHV6 play any role in the progression of HIV infection to AIDS? (iii) Is HHV6 involved in the pathogenesis of human 221
tumours? In short, the answers that are emerging are : “sometimes” for question (i), and “case unproven” for (ii) and (iii). Whereas most acute infections are asymptomatic, isolation of HHV6 from peripheral blood of infants with the roseola infantum (RI) syndrome, failure to isolate virus in the convalescent phase, and demonstration of HHV6 seroconversion in acute and convalescent sera, suggest that HHV6 is the major, if not the only, cause of RL8 This syndrome, also known as exanthem subitum, or sixth disease, consists of a non-specific febrile illness in infancy, with the appearance of a rash as the fever resolves. Hepatitis (fatal in one case), encephalitis, and the development of the haemophagocytic syndrome, have also been reported in infants.g*l o Primary HHV6 infection in an older child or adult has been associated with infectious mononucleosis-like and hepatitic illnesses. More severe consequencesof a herpesvirus infection might be expected in the immunosuppressed. HHV6 was isolated from the peripheral blood of a liver transplant recipient during a pyrexial illness with hepatitis, and the virus has been implicated in interstitial pneumonitis following bone marrow transplantation. Virus has also been isolated from the peripheral blood of renal transplant recipients, and serological evidence of reactivation of HHV6 has been associated with the development of severe rejection episodes in one study.l4 However, viral reactivation is likely to follow increased immunosuppression, and a role in graft rejection has yet to be proven. Interpretation of serological data in transplant patients is complicated by the observation that most patients undergoing primary CMV infections also have serological evidence of HHV6 infection or reactivation. Cross-absorption studies show that the anti-HHV6 response is not due simply to the presence of cross-reactive anti-CMV antibodies. l 5 The contribution, if any, of HHV6 reactivation to the morbidity induced by CMV infection has yet to be clarified. The tropism of HHV6 for CD4-positive T cells, and the lytic nature of such infection in vitro, has prompted speculation that activation of HHV6 in vivo may be a co-factor in the loss of CD4 cells and subsequent development of AIDS in HIV-infected individuals. Observations of HHV6-induced enhanced HIV-1 replication in dually infected CD4-positive cells in vitro support this hypothesis.16 The elegant demonstration of HHV6-induced expression of the CD4 molecule on CD8-positive cells, thereby
222
EDITORIAL
’
rendering those cells susceptible to HIV infection, * suggests a further mechanism of potentiation. However, others have reported suppression of HIV-1 replication by HHV6,18 and the in-vivo relevance of CD4- CD8-positive cells has yet to be established. Furthermore, serological evidence does not support the hypothesis that HHV6 reactivation plays an important role in the progression of HIV-1 associated disease, The isolation of HHV6 from patients with various lymphoproliferative diseases has led to a number of
attempts to implicate HHV6 as a cause of human cancers, but no convincing evidence has yet emerged. The HHV6 genome has occasionally been detected in lymphomatous tissue of B and T cell origin,20 but these results require careful interpretation, as the genome may also be found in normal lymph node tissue. W. L. IRVING
References
12. Ward K N, Gray J J, Efstathiou S. Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. J Med Virol 1989; 28: 69-72. 13. Carrigan D R, Drobyski W R, Russler S K, Tapper M A, Knox K K, Ash R C. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 1991;338: 147-149. 14. Okuno T, Higashi K, Shiraki K et al. Human herpesvirus 6 infection in renal transplantation. Transplantation 1990; 49: 519-522. 15. Irving W L, Ratnamohan M, Hueston L C, Chapman JR, Cunningham A L. Dual antibody rises to cytomegalovirus and human herpesvirus type 6 : frequency of occurrence in CMV infections and evidence for genuine reactivity to both viruses, J Infect Dis 1990; 161: 910-916. 16. Lusso P, Ensoli B, Markham P D et al. Productive dual infection of human CD4’ T Lymphocytes by HIV-I and HHV-6. Nature 1989;337 : 370-373. 17. Lusso P, De Maria A, Malnati M et al. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature 1991; 349: 533-535. 18. Carrigan DR, Knox KK, Tapper MA. Suppression of human immunodeficiency virus type 1 replication by human herpesvirus-6. JInfect Dis 1990; 162: 844-851. 19. Spira T J, Bozeman L H, Sanderlin K C et al. Lack of correlation between human herpesvirus-6 infection and the course of human immunodeficiency virus infection. J Infect Dis 1990; 161: 567-570. 20. Jarrett R F, Gledhill S, Qureshi F et al. Identification of human herpesvirus Gspecific DNA sequences in two patients with non-Hodgkin’s lymphoma. Leukemia 1988; 2 : 496-502.
’
1. Salahuddin SZ, Ablashi DV, Markham PD e f al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234: 596-601. 2. Lawrence GL, Chee M, Craxton MA, Gompels UA, Honess R W, Barrel1 B G. Human herpesvirus 6 is closely related to human cytamegalovirus. J Viroll990; 64: 287-299. 3. Pietroboni GR, Hamett GB, Bucens MR, HonessRW. Isolation of human herpesvirus 6 from saliva. Lancet 1988; 1 : 1059. 4. Fox J D, Briggs M, Ward P A, Tedder R S. Human herpesvirus 6 in salivary glands. Lancet 1990; 336: 590-593. 5. Kondo K , Kondo T, Okuno T, Takahashi M, Yamanishi K. Latent human herpesvirus 6 infection of human monocytes/ macrophages. JGen Virol1991; 72: 1401-1408. 6. Asano Y , Yoshikawa T, Suga S et al. Human herpesvirus 6 harbouring in kidney. Lancet 1989; 2 : 1391. 7 Briggs M,Fox J, Tedder R S. Age prevalence of antibody to human herpesvirus 6. Lancet 1988; 1: 1058-1059. 8. Yarnanishi K, Shiraki K, Kondo T et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. tancer 1988; 1:1065-1067. 9. Irving W L, Chang J, Raymond D R, Dunstan R, GrattanSmith P, Cunningham A L. Roseola infantum and other syndromes associated with acute HHV6 infection. Arch Dis Child 1990;65. 1297-1300. 10. Huang L-M, Lee C-Y, Lin K-H et al. Human herpesvirus-6 associated with fatal haemophagocytic syndrome. Lancet 1990; 336: 60-61. 1 1 Irving W L, Cunningham A L. Serologicaldiagnosisof infection with human herpesvirus type 6. BMJ 1990,300: 156-159. I
Department of Medical Microbiology and Public Health Laboratory, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH.
