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Relatively recently, the discovery and analysis of three new human herpesviruses, human herpesvirus (HHV)-6, HHV-7, and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as HHV-8, has contributed greatly to our understanding of the pathogenesis of several common dermatoses. HHV-6 and HHV-7 are closely related β-herpesviruses that have been linked with roseola (mostly HHV-6), severe drug eruptions (HHV-6), and pityriasis rosea (mostly HHV-7). KSHV is a γ-herpesvirus that is now believed to be the long sought after etiologic agent of Kaposi's sarcoma. The evidence for these skin disease associations and key findings from recent basic science investigations on viral pathogenesis are discussed in this review. In addition, possible therapeutic implications of these research studies are explored.
The family of human herpesviruses contains eight members and is subdivided into three subfamilies (Table I). These include the α-herpesviruses (herpes simplex virus types 1 and 2 and varicella-zoster virus), the β-herpesviruses [cytomegalovirus (CMV), human herpesvirus (HHV)-6, and HHV-7], and the γ-herpesviruses [Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as HHV-8]. These subfamilies are based upon similarities in viral genomes and biologic behavior. For example, the α-herpesviruses all cause blistering skin diseases, whereas the γ-herpesviruses are distinguished by their potential to induce cellular proliferation and malignancy. In this review, I will focus on the skin diseases caused by the three most recently described human herpesviruses, HHV-6, HHV-7, and KSHV. Because of their marked similarities, HHV-6 and HHV-7 will be discussed together.
Hhv-6 and hhv-7
Historical aspects
HHV-6 was discovered by Gallo and colleagues in 1986 (
). It was isolated from the peripheral blood lymphocytes of six individuals with lymphoproliferative disorders. HHV-6 was named human B-lymphotropic virus, or HBLV, because it was initially found within B cells of infected individuals; however, subsequent work revealed that CD4+ T cells were the major cell type infected by HHV-6 (
). Serendipitously, these investigators noted cytopathic effects in cultures of activated CD4+ T cells isolated from a healthy individual. This finding led to isolation of HHV-7 and further ultrastructural and genetic characterization. Of note, the initials of this healthy individual were R.K., and designation of HHV-7 as RK virus, or an RK HHV-7 strain, is sometimes mentioned in the virology literature. The genomes of HHV-7 and both variants of HHV-6 are closely related, with 20%-75% nucleic acid homology depending on the genes being compared (
HHV-6 and HHV-7 are both ubiquitous herpesviruses. Most commonly, HHV-6 infects infants between the ages of 3 and 6 mo as protection from maternal antibodies wanes (
). Children with roseola typically present with high fever, usually without obvious signs of upper respiratory infection. The onset of the rash classically appears on the third day of fever, often coinciding with resolution of the fever. The rash of roseola is characterized by coin-sized erythematous macules or slightly elevated papules on the head and neck (Figure 1a). Primary infection with HHV-7 is most often asymptomatic; however, it can also cause a roseola-like illness in patients (
Figure 1Clinical examples of the skin diseases associated with HHV-6, -7, and -8 infection.(A) Roseola, most often associated with HHV-6 primary infection. (B) PR, purported to be associated with reactivation of HHV-7. (C) KS, characterized by tumor spindle cells latently infected with KSHV, also known as HHV-8.
Human herpesvirus 7 in patients with pityriasis rosea. Electron microscopy investigations and polymerase chain reaction in mononuclear cells, plasma and skin [see comments].
), a common papulosquamous disease that most often occurs in otherwise healthy young adults (Figure 1b). Specifically, HHV-7 DNA was found in 12 of 12 fresh lesional skin biopsies, in 12 of 12 peripheral blood mononuclear cell (PBMC) preparations, and in 12 of 12 cell-free serum samples isolated from PR patients. By contrast, HHV-7 DNA was detected in no skin specimens, in 44% of PBMC, and in no sera from healthy individuals. These investigators have also shown increased serum levels of IFN-α in PR patients, indicative of acute viral infection, and viral cytopathic changes noted on culture of PR PBMC. In summary, these data indicated that HHV-7 reactivation was occuring during PR.
Subsequent to these initial reports, however, other research teams have not been successful in establishing a definitive link between PR and HHV-7 (
found evidence of HHV-7 antibody increases in a few (but not in most) PR patients studied.
We have recently reported preliminary findings in abstract form on the detection of both HHV-7 and HHV-6 DNA by sensitive nested polymerase chain reaction (PCR) in skin, cell-free plasma, cell-free serum, and saliva from most patients with PR.
Watanabe et al. Pityriasis rosea (PR) is associated with reactivation of both human herpesvirus (HHV)-7 and -6 in blood. J Invest Dermatol 114:784, 2000 (abstr.)
Plasma and serum samples from healthy individuals were always negative. Viral localization studies are currently underway to help expand and understand the significance of our PCR results.
Recently, three patients have been reported with severe drug–induced hypersensitivity syndromes associated with systemic HHV-6 reactivation (
). All three had extensive exfoliative dermatitis. Allopurinol and sulfasalazine were identified as the medications that triggered the eruptions. The precise role of HHV-6 in these types of cases needs to be further explored.
Therapeutic implications and future research directions
The HHV-6 disease associations with roseola in children and widespread organ involvement in immunosuppressed individuals are well established. Unfortunately, acyclovir and its derivatives have little antiherpesviral activity against HHV-6 and HHV-7 (
). Foscarnet, ganciclovir, and cidofovir have some activity at high concentrations, but all of these medications are of limited practical use because of the need to administer them intravenously or the potentially worrisome side-effects. Thus, patients with active HHV-6 replication and roseola should not be treated with antiherpesviral therapy. These drugs, however, should be considered in patients with end organ dysfunction or widespread systemic disease. At this time, patients with PR, whether the association with HHV-7 is confirmed or refuted, should also not be treated with antiherpesviral therapy. Further study is needed to determine the roles of herpesviruses in the etiologies of both PR and severe drug-induced hypersensitivity reactions.
Kshv
Historical aspects
Moritz Kaposi, a Hungarian born dermatologist, first described idiopathic multiple pigmented sarcoma of the skin in 1872 (Figure 1c) (
). Interestingly, Kaposi was first to suggest a possible infectious etiology for Kaposi's sarcoma (KS). With the epidemiologic evidence of KS clustering in characteristic populations and clinical disease settings (especially as documented in the HIV+ gay community), the search for a possible infectious cause of KS intensified (
), yet evidence for causality was subsequently not substantiated.
In December 1994, the husband and wife research team of Yuan Chang and Patrick Moore at Columbia University reported on the isolation of novel herpesviral DNA sequences in KS tissue, but not in surrounding normal skin (
). The DNA was detected in a KS genomic library using the powerful molecular biologic method of representational difference analysis, a technique that combines features of subtractive hybridization and PCR (
). Thus, KSHV is found within lesions of AIDS-associated, classical, endemic, and iatrogenic KS, as well as in KS involving skin, lymph nodes, lungs, or the gastrointestinal tract. Because of this tight disease association, this new virus became known as KSHV (currently the preferred term), although some refer to it as HHV-8.
Epidemiology and disease associations
The detection of antibodies specific for KSHV has yielded insight into the geographic distribution of this virus. Current assays show that approximately 95% of KS patients (all clinical types) are seropositive for KSHV (
The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
). Interestingly, most studies have also shown relatively high levels of KSHV seropositivity in populations where KS is prevalent. For example, HIV+ gay men, sub-Saharan Africans, and individuals from southern Italy who have no clinical evidence of KS, yet all of whom represent “at risk” populations for KS, have a high incidence of KSHV seropositivity (approximately 30%-40%, 50%-60%, and 15%-30%, respectively) (
The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
). By contrast, specific individuals at low risk of developing KS (e.g., HIV-infected women and children from the U.S.A.) have a low prevalence of KSHV-specific antibodies (
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women.
The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection.
). These patients have been described as having an infectious mononucleosis-like syndrome consisting of fever, lymphadenopathy, and splenomegaly. No rash has yet been reported with primary KSHV infection. By contrast to this description, Luppi et al recently reported primary KSHV infection following transplantation; two patients experienced bone marrow failure within months after each receiving transplanted kidneys from the same KSHV-infected donor (
Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.
), suggesting a possible basis for fecal-oral or oral-fecal transmission of KSHV. There are also clear studies that suggest nonsexual routes of KSHV transmission (e.g., via saliva), especially in African countries (
). In general, herpesviruses are frequently detected in saliva of infected individuals. KSHV is no different, in that this virus has been readily detected in the saliva of most KS patients and in 15%-33% of HIV+ patients without KS (
Frequent detection of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in saliva of human immunodeficiency virus-infected men: clinical and immunologic correlates.
). The discrepancy in the mode of KSHV transmission between developed and underdeveloped nations is similar to that observed with hepatitis A virus infection, and suggests that poor hygiene may increase the risk of acquiring KSHV. Finally, sequence differences among KSHV in different parts of the world suggest the existence of several KSHV strains (
Comparison of genetic variability at multiple loci across the genomes of the major subtypes of Kaposi's sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame K15 alleles at the right-hand end.
High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations.
). It is theoretically possible that different KSHV strains may have different routes of transmission and clinical relevance. Further study is needed to determine this issue as well as other specific variables involved in the transmission of KSHV and, in particular, studies are needed that examine these factors in different parts of the world.
In addition to KS, Chang and Moore initially detected KSHV DNA in three of 27 cases of AIDS-associated lymphomas (
). On subsequent analysis, it was determined that these patients had primary effusion lymphoma (PEL), a rare disease previously known as body cavity-based B cell lymphoma (
). Patients present with collections of serous fluid, usually with no solid tumor mass, within the pleural, pericardial, or peritoneal cavities; the fluid contains malignant B cells that are infected with KSHV and often dually infected with EBV. The original report by Cesarman et al that definitively linked KSHV with PEL was confirmed by many other studies (
). Importantly, several KSHV-infected B cell lines have been isolated from patients with PEL and have allowed investigators to study KSHV gene expression and the viral life cycle in detail (
KSHV has also been linked with confidence to the plasmablastic variant of Castleman's disease (CD), also called multicentric angiofollicular lymphoid hyperplasia (
). This variant of CD is typically (but not always) associated with HIV disease. Clinically, patients with CD present with fever, lymphadenopathy, and splenomegaly, whereas histologic examination of affected tissues shows polyclonal lymphoid hyperproliferation with vascular hyperplasia.
Other than KS, PEL, and CD, there are a fairly large number of reports on the PCR detection of KSHV DNA in a wide variety of diseases (reviewed in
). Some of these include angiosarcoma, a variety of lymphoproliferative disorders, basal cell carcinoma, pemphigus vulgaris and foliaceus, multiple myeloma, and sarcoidosis. Subsequently, however, many teams of independent investigators have been unable to substantiate the claims of these studies, adding strength to the conclusion that KSHV is definitively linked to only three diseases: KS, PEL, and CD. This experience has proven that rigorous evaluation of possible future KSHV disease associations is needed. Because of the great potential for false positive PCR results, it will be important to prove or disprove initial PCR reports by performing viral localization studies within tissue (e.g., electron microscopy, in situ hybridization, immunostaining) and by examination of patients' sera for KSHV antibodies.
Pathogenesis of KS
Using the techniques of in situ PCR, in situ hybridization, electron microscopy, and immunohisto chemistry, KSHV is localized to tumor spindle cells, lymphatic endothelial cells lining slit-like vascular spaces, and tumor-infiltrating leukocytes (
), although more studies will be required to identify the nature of these cells. The localization studies confirmed the earlier PCR studies and added further insight into the role that KSHV may be playing in the pathogenesis of KS by identifying specific cellular targets for viral infection.
Most studies have now established that KSHV can be found in the blood of over half of all KS patients (
), although there are a few reports of KSHV within circulating CD34+ cells and CD8+ T cells. Like EBV, B cells appear to be the major latent reservoir cell for KSHV in blood. Interestingly, the ability to detect KSHV DNA in peripheral blood leukocytes from individuals without KS is predictive for future development of KS (within 2–4 y) (
). Taken together, these data suggest that reactivation from latency is occuring in peripheral blood B cells, perhaps leading to “seeding” of virus within dermal lymphatics (Figure 2). Multiple factors are likely to be involved in regulating latent-to-lytic switching of KSHV and eventual KS development in a given individual, some of which include age, sex hormones, concomitant HIV disease, pro-inflammatory and angiogenic cytokines and growth factors, immunosuppressive drugs, and perhaps other processes that impair cell-mediated immunity (Figure 2). Interestingly, we have recently provided evidence that tissue hypoxia (
) may also contribute to the onset of KS. Importantly, a complete understanding of this variety of factors may lead to specific prophylactic interventions in KSHV-infected individuals at risk for developing KS.
Like EBV, KSHV belongs to the γ-herpesvirus subfamily. These herpesviruses share sequence homology and the ability to infect and transform lymphocytes (Table I). Although the EBV genes involved in cellular transformation are well known, there are no homologous genes within the KSHV genome (
). Instead, KSHV, which contains over 80 open reading frames, has the striking feature of having many genes that encode for proteins with interesting cellular homologs (Table II) (
). Thus far, LANA, v-cyclin, vFLIP, and kaposin are the only KSHV-encoded genes shown to be expressed in latently infected KS tumor spindle cells (Table II) (
Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies.
The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells.
The latent nuclear antigen of kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene hras transforms primary rat cells.
), major tumor suppressor proteins. v-Cyclin has been shown to stimulate resting cells through the cell cycle by overcoming normal Rb-mediated suppression of the G1, or resting, phase of the cell cycle (
). Identifying the precise functions of these potential viral oncoproteins, and determining how they interact with one another, should lead to a more complete understanding of how KSHV stimulates cell growth.
Table IClassification of known human herpesviruses
Variable host range, relatively short reproductive cycle, rapid spread in culture, efficient destruction of infected cells, capacity to establish latent infections primarily (but not exclusively) in sensory ganglia
β
Cytomegalovirus HHV-6 HHV-7
Restricted host range, relatively long reproductive cycle, slow growth in culture, infected cells become enlarged, carrier cultures easily established
γ
Epstein-Barr virus KSHV (HHV-8)
Restricted host range, replicate in lymphoblastoid cells and sometimes in epithelioid and fibroblastic cells, latent virus frequently detected in l ymphoid tissue, associations with malignancies
Therapeutic implications and future research directions
Knowledge of the KSHV life cycle has important therapeutic implications for KSHV-infected individuals. For example, all known antiherpesviral medications, including acyclovir and its derivatives, foscarnet, cidofovir, and ganciclovir, act by blocking active viral replication. Because of this, they are likely to have no significant impact on existing KS lesions, where the majority of tumor spindle cells are latently infected with KSHV. By contrast, these drugs may be expected to prevent onset of new lesions, or perhaps prevent the onset of KS in those who are infected with KSHV. Indeed, several retrospective analyzes suggest that HIV+ patients who have taken foscarnet or ganciclovir have a lower incidence of KS when compared with those who have not taken these drugs (
). Past use of acyclovir was not protective for future development of KS. Interestingly, but not surprisingly, these epidemiologic observations have been bolstered by laboratory reports showing that foscarnet, ganciclovir, and cidofovir, but not acyclovir, block lytic induction of KSHV in phorbol ester-stimulated PEL cell lines (
Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents.
). The fascinating observation that KS can develop during immunosuppressive therapy, and regress following withdrawal of immunosuppressive agents, strongly suggests an important role for cell-mediated immunity in the control of KSHV-induced disease. This is true for EBV, where loss of EBV-specific immunity is linked to the onset of EBV-associated disease (
). In HIV-infected individuals, the common occurrence of KS improvement in patients receiving highly active antiretroviral therapy is likely due to improved cellular immunity, since these drugs have no direct effect on KSHV replication (
Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents.
). Delineating the determinants of KSHV-specific cellular immunity should prove useful for both therapeutic and preventive purposes. For example, advances in this area may lead to strategies designed to boost KSHV-specific immunity in KS patients, or be used to design vaccines to prevent KSHV infection.
Although much has been learned in a relatively short period of time, much work remains to be done in order to delineate the precise role of KSHV in the pathogenesis of KS and other diseases. In vitro infection of normal cells with KSHV has proven difficult (
). There is, as of yet, no robust system for studying de novo KSHV infection and the functional effects induced by infection, although several investigators have reported success in infecting endothelial cells, either in the absence (
). No good animal model for KS exists, i.e., one that incorporates KSHV infection. Injection of PEL cells into immunodeficient mice leads to lymphoma-like tumor formation; however, no transfer of KSHV infection to murine cells occurs (
). Interestingly, KSHV-related viruses have recently been identified in nonhuman primates, with one report linking viral infection with the KS-like disease retroperitoneal fibromatosis in the monkey (
). The usefulness of these findings as potential models for KS remains to be determined. Obviously, development of a small animal model for KS that incorporates KSHV infection will prove invaluable for studying KS pathogenesis and for testing new therapeutic reagents.
ACKNOWLEDGMENTS
I thank Harry Schaefer for helping to prepare the figures, Robert Silverman for the picture of the child with roseola, and Takahiro Watanabe for helpful discussions.
References
Ambroziak J.A.
Blackbourn D.J.
Herndier B.G.
et al.
Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients.
In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences.
The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells.
Human herpesvirus 7 in patients with pityriasis rosea. Electron microscopy investigations and polymerase chain reaction in mononuclear cells, plasma and skin [see comments].
The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women.
The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.
Frequent detection of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in saliva of human immunodeficiency virus-infected men: clinical and immunologic correlates.
Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.
Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection.
Comparison of genetic variability at multiple loci across the genomes of the major subtypes of Kaposi's sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame K15 alleles at the right-hand end.
The latent nuclear antigen of kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene hras transforms primary rat cells.
Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies.
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents.
High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations.
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