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The history of the identification of human herpesvirus 8 (HHV-8; also
known as Kaposi sarcoma herpesvirus [KSHV] or
Kaposi sarcoma [KS] virus) was unique among the Herpesviridae insofar
as the virus was initially “discovered” purely
on a molecular biologic basis using a powerful detection technique.1 Working
with tissue from HIV- infected individuals with KS, Chang and colleagues
used a technique referred to as “representational difference
analysis” to identify disease-specific DNA sequences in
KS tissue. On DNA sequence analysis, the deduced amino acid sequences
were found to have strong homology to proteins from the gamma herpesvirus subfamily,
the subfamily of the Herpesviridae that includes
Epstein-Barr virus (EBV). This observation was striking in view
of the known ability of EBV to persist in lymphocytes, immortalize
cells, and produce human malignancies (Burkitt lymphoma and nasopharyngeal
carcinoma). Hence, the novel gamma herpesvirus, HHV-8, appeared
to be a new herpesvirus associated with human malignancy, Kaposi
sarcoma. Eventually HHV-8 was cultivated in tissue culture, proving
that these DNA sequences corresponded to a morphologically identifiable
viral particle.2
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The epidemiology of primary human herpesvirus 8 (HHV-8) infection
appears to vary considerably worldwide. The routes of acquisition
of infection and mechanisms responsible for person-to-person transmission
remain uncertain. After the virus was initially discovered, the
unique role it seemed to play in inducing malignant disease in HIV-infected
patients suggested that the primary route of transmission of HHV-8
was through sexual contact, particularly among gay men. However,
more recent evidence suggests that other routes of infection exist,
including transmission by saliva.4 A cross-sectional
study of the seroprevalence of HHV-8 in children and adolescents
in the United States indicated a prevalence of approximately 1%.5 There
appears to be considerable regional variation in prevalence in the
United States. In a population of children in south Texas, the seroprevalence
was 26%, strongly suggesting that nonsexual modes of transmission
predominate.6 In sub-Saharan Africa, prevalence in
children is even higher, approaching 60% in some studies (reviewed
in 7). There are reports of maternal-to-child transmission that
suggest the possible of vertical infection (reviewed in 8), but the
mechanisms of transmission and clinical manifestations in newborns
are unclear. HHV-8 can also be transmitted by blood transfusion.9 As
serologic and nucleic acid-based diagnostics tests become more widely
available, a better assessment of the worldwide seroepidemiology
of HHV-8 infection will become feasible.
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Structurally, human herpesvirus 8 (HHV-8) consists of a prototypical
enveloped particle, morphologically similar to other herpesviruses.
The virus presumably establishes latent infection following primary
infection, although the site(s) of latency are unknown. Evolutionarily,
HHV-8 appears to have undergone considerable recombination with
host genes, and the viral genome contains a variety of transduced
cellular oncogenes and chemokine homologs that are probably important
in the pathogenesis of KS.3 It is estimated that
10% of the genes encoded by HHV-8 promote KS development
due to mitogenic, antiapoptotic, chemoattractive, angiogenic, or
transforming activities.
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Clinical Manifestations
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Most primary infections with human herpesvirus 8 (HHV-8) are probably
asymptomatic, although the clinical course of primary symptomatic
HHV-8 infection in immunocompetent children with fever and rash
was more recently described.10 The rash first appeared
on the face and gradually spread to the trunk, arms, and legs. It
initially consisted of discrete red macules that blanched with pressure
and eventually became papular. The median duration of the rash was
6 days; fever persisted for a median of 10 days, and some children
had high fever (temperature, 39°C). An upper respiratory tract infection
occurred in most, and a lower respiratory tract infection appeared
in one third, although major respiratory complications did not occur
during the course of primary HHV-8 infection.
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Prior HHV-8 infection appears to be necessary, but not sufficient, for
the development of Kaposi sarcoma (KS), which is a multifocal vascular
neoplasm involving skin, visceral organs, and lymph nodes. Lesions
histopathologically contain distinctive proliferating cells, so-called “spindle” cells,
as well as activated endothelial cells, fibroblasts, smooth muscle
cells, and infiltrating inflammatory cells. Three variants of KS
are described11: “classical” KS,
which is chiefly an indolent, slowly progressive form of KS seen
in elderly, HIV-negative Mediterranean men; “endemic” KS,
a variant seen in Africa (including a “lymphadenopathic” form
seen predominantly in young children); and “epidemic” KS,
seen in HIV-infected patients. All variants are associated with
HHV-8. The factors responsible for malignant transformation of HHV-8-infected endothelial
cells into tumor are unknown.
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Other malignant diseases have been associated with HHV-8, including
multicentric Castleman disease (MCD), a lymphoproliferative syndrome
associated with HIV infection, and another AIDS-associated malignancy,
primary effusion lymphomas (PEL) (eTable 313.1). HHV-8
is causally related to these tumors in HIV-negative patients as
well. Other malignancies, including skin cancer and multiple myeloma,
have been associated with HHV-8 in the literature, but these reports
are controversial, and the causal link remains unproven (eTable 313.1). Links between HHV-8 and pemphigus,
sarcoidosis, and Kikuchi disease have been postulated,11 and
more recently there have been associations reported between HHV-8
and hemophagocytic syndromes.12
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Diagnosis and
Therapy
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In the absence of standardized serologic assays, serodiagnosis
of human herpesvirus 8 (HHV-8) infection is problematic. Tissue
from any case of Kaposi sarcoma (KS), primary effusion lymphomas
(PEL), or multicentric Castleman disease (MCD) that is encountered
in a child should probably be investigated for the presence of HHV-8
DNA sequences, in collaboration with a reference laboratory. HIV
serology should also be performed in such patients. AIDS-associated KS
has been reported to regress following administration of highly
active antiretroviral therapy (HAART), suggesting that reversal
of immunosuppression may promote resolution of the tumor. No controlled
trials of specific antiviral therapy have been conducted for KS,
although treatment with either oral or intravenous ganciclovir (GCV)
was associated with a strongly reduced risk of KS in AIDS patients
prior to the advent of HAART, suggesting an antiviral effect of
GCV against HHV-8. Although these are intriguing data, chemotherapy
and radiation therapy remain the mainstays of therapy for most cases
of KS, as well as other HHV-8-associated tumors.