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In This Issue: The Human Herpesviruses and Pityriasis Rosea: Curious Covert Companions?

2002; Elsevier BV; Volume: 119; Issue: 4 Linguagem: Inglês

10.1046/j.1523-1747.2002.05558.x

1523-1747

Caroline Breese Hall,

Parvovirus B19 Infection Studies

Hark, ye doctors of microbial mastery! The Darwinian Domos of the medical world are indeed the invisible instigators of infectious diseases. Not only have they been indicted as the cause of such common maladies as dyspepsia, peptic ulcer, and coronary artery disease, but now the Christmas Tree rash with its herald patch, pityriasis rosea. In this issue, Watanabe and colleagues add significantly positive weight to the vacillating balance of the causal role in pityriasis rosea of the human herpesviruses 6 and 7 (HHV6 and HHV7). 150 years ago, the French dermatologist Gibert appropriately named this rash for its scale of bran ‘pityriasiform’, and its rose-red hue, ‘rosea’. So distinctive and commonly observed was this rash that it was inevitable that the pursuit of the protagonist of pityriasis rosea began decades ago and subsequently centered on an infectious agent, particularly a virus (Kempf and Burg, 2000Kempf W. Burg G. Pityriasis rosea- a virus-induced skin disease? An update.Arch Virol. 2000; 145: 1509-1520Crossref PubMed Scopus (36) Google Scholar). Over the last 5–6 years studies have focused on HHV6 and primarily HHV7 (Drago et al., 1997Drago F. Ranieri E. Malaguti F. Battifoglio M. Losi E. Rebora A. Human herpesvirus 7 in patients with pityriasis rosea.Dermatol. 1997; 195: 374-378Crossref PubMed Scopus (140) Google Scholar, Kempf et al., 1999Kempf W. Adams V. Kleinhans M. Burg G. Panizzon R. Campadelli-Fiume G. Nestle F. Pityriasis rosea is not associated with human herpesvirus 7.Arch Dermatol. 1999; 135: 1070-1072Crossref PubMed Scopus (84) Google Scholar). Their contrasting conclusions enhanced the interest, but not the clarity, of HHV6 and HHV7′s causal role. To understand why the research path attempting to assign disease to these human herpesviruses is often convoluted and confused, one must consider the character and conundrums of HHV6 and HHV7. HHV6 was initially isolated in 1986 from patients with AIDS and lymphoproliferative disorders (Salahuddin et al., 1986Salahuddin S. Ablashi D. Markham P. Josephs S. Sturzenegger S. Kaplan M. Halligan G. Biberfeld P. Wong-Staal F. Kramarsky B. Gallo R. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders.Science. 1986; 234: 596-601Crossref PubMed Scopus (1215) Google Scholar). Two years later,Yamanishi et al isolated HHV6 from four infants with roseola (Yamanishi et al., 1988Yamanishi K. Okuno T. Shiraki K. Takahashi M. Kondo T. Asano Y. Kurata T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum.Lancet. 1988; 1: 1065-1067Abstract PubMed Scopus (1280) Google Scholar). HHV7 was subsequently identified serendipitously in the cells of a healthy adult in 1990 by Frenkel and colleagues (Frenkel et al., 1990Frenkel N. Schirmer E. Wyatt L. Katsafanas G. Roffman E. Danovich R. June C. Isolation of a new herpesvirus from human CD4+ T cells.Proceed Natl Acad Sci USA. 1990; 87: 748-752Crossref PubMed Scopus (413) Google Scholar). The circumstances of the discovery of these two viruses were prophetic for our current understanding of their clinical roles. HHV6 is clearly associated with clinical primary infection manifested by abrupt high fever and varying nonspecific signs, as well as ‘the rash of roses’ of exanthem subitum in children primarily between 6 and 24 months of age (Hall et al., 1994Hall C. Long C. Schnabel K. Caserta M. McIntyre K. Costanzo M. Knott A. Dewhurst S. Insel R. Epstein L. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation.N Engl J Med. 1994; 331: 432-438Crossref PubMed Scopus (506) Google Scholar;Yamanishi, 2001Yamanishi A. Human herpesvirus 6 and human herpesvirus 7.in: Knipe D. Howley P. Fields’ Virology. Lippincott Williams & Wilkins, Philadelphia2001: 2785-2801Google Scholar). In adults, clinical manifestations have been primarily associated with reactivation in highly immunocompromised hosts. HHV7, however, primarily remains a covert bystander. Primary infection and clinical disease have rarely been recognized (Black and Pellett, 1990). The few reported cases suggest clinical primary infection is similar to HHV6 and may account for second cases of roseola. These two β-herpesviruses are remarkably similar, the closest virologic siblings among the human herpesvirus family (Yamanishi, 2001Yamanishi A. Human herpesvirus 6 and human herpesvirus 7.in: Knipe D. Howley P. Fields’ Virology. Lippincott Williams & Wilkins, Philadelphia2001: 2785-2801Google Scholar;Black and Pellett, 1999Black J. Pellett P. Human Herpesvirus 7.Rev Med Virol. 1999; 9: 245-262Crossref PubMed Scopus (104) Google Scholar). Both are acquired in early childhood, resulting in universal infection. Both subsequently become latent in peripheral blood mononuclear cells, saliva, and other sites. The primary target for both viruses is the mature CD4+ T-cell, which is the cell receptor for HHV7. Although HHV7 antigen expressing cells are detectable in a wide number of other sites, including skin, lungs, mammary glands, liver, and kidney, HHV6 has the broader cellular tropism. This may relate to the essential membrane receptor for HHV6 being CD46 which is present on the surface of all nucleated cells (Yamanishi, 2001Yamanishi A. Human herpesvirus 6 and human herpesvirus 7.in: Knipe D. Howley P. Fields’ Virology. Lippincott Williams & Wilkins, Philadelphia2001: 2785-2801Google Scholar;Black and Pellett, 1999Black J. Pellett P. Human Herpesvirus 7.Rev Med Virol. 1999; 9: 245-262Crossref PubMed Scopus (104) Google Scholar). From these multiple sites both viruses may reactivate. The importance of the similarity of curriculum vitae of HHV6 and HHV7 is (1) the two are closely related virologically (2) both cause universal infection early in life (3) each becomes latent subsequently, and (4) they reactivate in older children and adults. Thus, studies associating HHV6 and HHV7 disease in adults may be confounded by the universal presence and detection of these viruses from multiple sites, and presumably if they are responsible for associated clinical manifestations, they are the result of reactivation. Our understanding of the pathogenesis of reactivation, however, has been limited, as has been the technology to differentiate productive (lytic) from latent or quiescent infection of persisting virus. Watanabe and colleagues have avoided some of these issues by employing not only nested polymerase chain reaction (PCR) to detect HHV6 and 7 DNA in skin, peripheral blood mononuclear cells, serum, and saliva, but additionally used in situ hybridization to identify viral mRNA expression and attempted visualization of herpes virions in skin lesions by transmission electron microscopy. HHV7 DNA was found in 93% of the lesions from pityriasis rosea patients and also in 86% of their nonlesional skin samples. HHV6 DNA was also found in both lesional and nonlesional skin samples. DNA of both viruses could also be detected in the few lesional and nonlesional samples of controls, indicating the lack of diagnostic specificity of HHV6 or HHV7 DNA detection. But they further demonstrated mRNA expression, and thus active replication, of HHV7 in mononuclear cells of lesional skin specimens in 8 of 8 patients with pityriasis rosea, and HHV6 in 6 of the 8 specimens, but in only 1 of 8 skin biopsies of healthy and psoriasis controls. Of particular note, however, is the detection of HHV7 and HHV6 DNA in 100% and 88%, respectively, of serum samples from pityriasis rosea patients, but from none of the serum specimens from controls. These are new findings which potentially offer new insights into the conundrum of the persistence of HHV6 and HHV7 subsequent to primary infection. Presumably the productive infection arises from reactivation since these patients most likely have been infected with both of these viruses years previously in early childhood, although this was not confirmed serologically. However, the manifestations in these pityriasis patients associated with reactivation are singular for hosts with normal immunity. The detection of HHV6 and HHV7 in the serum of these subjects with pityriasis rosea indicated concurrent viremia and systemic infection. Viremia in previously infected individuals, unless immunocompromised, is highly unusual (Hall et al., 1994Hall C. Long C. Schnabel K. Caserta M. McIntyre K. Costanzo M. Knott A. Dewhurst S. Insel R. Epstein L. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation.N Engl J Med. 1994; 331: 432-438Crossref PubMed Scopus (506) Google Scholar;Yamanishi, 2001Yamanishi A. Human herpesvirus 6 and human herpesvirus 7.in: Knipe D. Howley P. Fields’ Virology. Lippincott Williams & Wilkins, Philadelphia2001: 2785-2801Google Scholar;Black and Pellett, 1999Black J. Pellett P. Human Herpesvirus 7.Rev Med Virol. 1999; 9: 245-262Crossref PubMed Scopus (104) Google Scholar). Furthermore, viremia with these viruses in our experience has been consistently associated in immunologically normal hosts with appreciable fever and systemic symptoms, which were not present in these subjects. This is additionally confounded by the statement in the methods that the authors only evaluated samples of serum that had a β-globin positive control. Since this implies the presence of white blood cells, the serum was not cell free, and the question of possible contamination rises. Yet the serum from the control subjects which presumably were also only assayed if β-globin controls were present, did not contain the viral DNA, despite HHV7 DNA being present in 82% of their peripheral blood mononuclear cells. These results are not easily explained. Concurrent viral isolation from serum samples could possibly have helped explain the above results, as well as in situ hybridization of nonlesional samples from the pityriasis patients or some further quantitative analysis of the type of mononuclear cell infiltration (i.e. T-cell, monocyte) in these nonlesional samples. Another intriguing aspect of this paper is the potential interaction of HHV6 and HHV7 which has been demonstrated in vitro by experiments showing that HHV7, but not HHV6, may be reactivated from latently infected blood mononuclear cells by T-cell activation. However, latent HHV6 could be recovered when coinfection with HHV7 was established, suggesting HHV7 can provide a transacting function allowing the reactivation of latent HHV6 (Tanaka-Taya et al., 2000Tanaka-Taya K. Kondo T. Nakagawa N. Inagi R. Miyoshi H. Sunagawa T. Okada S. Yamanishi K. Reactivation of human herpesvirus 6 by infection of human herpesvirus 7.J Med Virol. 2000; 60: 284-289Crossref PubMed Scopus (43) Google Scholar;Katsafanas et al., 1996Katsafanas G. Schirmer E. Wyatt L. Frenkel N. In vitro activation of human herpesviruses 6 and 7 from latency.Proc Natl Acad Sci, USA. 1996; 93: 9788-9792Crossref PubMed Scopus (137) Google Scholar). We have also shown in normal children that reactivation of one virus may occur with primary infection of the other as demonstrated by concurrent isolation of HHV6 and HHV7 from the peripheral blood mononuclear cells of the children. Most frequently primary HHV7 infection appears to elicit HHV6 reactivation, although the opposite may also occur. These children, however, have consistently shown systemic illness with high fevers. The salient and piquant findings of this article further suggest that the potential interaction of these two viruses may be an important mechanism of pathogenesis. Second, the reactivation of both viruses associated with viremia in hosts with normal immunity is singular. This could possibly result from primary infection of HHV7 with reactivation of HHV6. However, this would seem unlikely in view of the epidemiologic data demonstrating that essentially all adults have had primary infection with both of these viruses as children. More important is the question of whether these findings of the association of HHV6 and HHV7 with pityriasis rosea explain and expand our clinical observations of this disease: Can they explain what triggers the abrupt occurence of this exanthem which becomes widespread in a host harboring both viruses since early childhood? Could this represent a particular host susceptibility with the necessary cofactors of both viruses being simultaneously present or a stress to the skin that results in local diminished control of latent virus and local reactivation? Do these capricious viruses explain the small number of recurrent pityriasis cases (estimated at 3%) as being related to repetitive episodes of reactivation? Conversely, can the 97% lack give clues to the mechanism that keeps these parasitic viruses asymptomatic since early childhood? Could recurrent cases or the clinical variations of pityriasis rosea possibly be associated with the reactivation of different strains of HHV6, variant A and variant B, or of a difference in the viral loads of HHV7 vs. HHV6? Are the characters of these two viruses, as we currently view them, compatible with pityriasis rosea's age, predilection, prolonged course, and the herald patch that lights the Christmas Tree, but remains its most prominent star? There may be no consensus on whether the answer is yes of no, but certainly as to whether more research is necessary.