Human herpesvirus 8 infection

Human herpesvirus 8, also known as Kaposi sarcoma-associated herpesvirus, is etiologically associated with Kaposi sarcoma and other rare malignancies. Human herpesvirus 8 infection is common in certain areas of Africa and Italy, but occurs in only 0% to 15% of adult populations in North America and Europe. Reports of human herpesvirus 8 prevalence of 3% to over 50% among children in Central Africa, Brazil, and South Texas suggest that horizontal transmission of human herpesvirus 8 occurs among children. Primary human herpesvirus 8 infection in immunocompetent children is associated with a fever and maculopapular rash. Curr Opin Pediatr 2003, 15:85–91 © 2003 Lippincott

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is a human gammaherpesvirus recognized primarily by its association with several human tumors ( Table 1). Analysis of HHV8 terminal repeats shows clonal expansion in Kaposi sarcoma (KS) [1]. Establishment of stable HHV8 monoinfected cell lines suggests that cells are immortalized and possibly transformed by HHV8 [2][3][4][5]. These cell lines can grow in semi-soft agar [6], suggesting that they have lost contact inhibition and are indeed transformed. Both subcutaneous and intravenous inoculations of HHV8-infected cell lines into nude mice cause tumors, further demonstrating HHV8 tumorigenicity [6,7]. Recently, stable and direct cellular transformation of human primary endothelial cells by HHV8 has been achieved [8,9], providing direct evidence of the oncogenic nature of HHV8.

HHV8 and human cancers
Human herpesvirus 8 was initially discovered by representational difference analysis of KS from a patient with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) [10]. Since the discovery of HHV8, many studies indicate an etiologic role of HHV8 in the development of KS [11,12]. Human herpesvirus 8 DNA is detected in all clinical forms of KS and is specifically localized to KS lesions [10,13-18]. The epidemiology of HHV8 is very similar to that previously established for KS. In North America and Europe, anti-HHV8 antibodies are primarily found in persons with KS or at high-risk for KS, such as homosexual men, but rarely in persons at low risk for KS, such as sexually transmitted disease-free general blood donors [2,19-21]. The geographic distribution of HHV8 infection in the general populations is also very similar to the incidence described for KS , and a viral interferon regulatory factor (vIRF) that causes cellular transformation through inhibition of interferon signaling and down-regulation of cyclindependent protein kinase inhibitor (CDKI) p21 WAF1/CIP1 [81, [102][103][104][105][106][107]. Thus, HHV8 lytic replication produces viral products that can potentially promote cellular proliferation in tumor cells.

Epidemiology of HHV8 infection
Like all herpesviruses, HHV8 infection persists for the life of the host following primary infection. The presence of HHV8 antibodies confirms past, and persistent, HHV8 infection. Therefore, HHV8 antibody seroprevalence increases linearly with age and reflects the cumulative incidence of HHV8 infection. The prevalence of HHV8 infection in blood donors and the general population varies substantially by geographic region. Human herpesvirus 8 prevalence in the general population in North America and Europe is relatively low, ranging from 0% to 15% [2,21, [108][109][110][111][112][113][114][115], though some studies have reported rates as high as 20% [116]. In Mediterranean and Eastern European countries, regions where there are historically high rates of KS, HHV8 prevalence is substantially higher, ranging from 4% to 24% [2, [117][118][119][120]. The prevalence of HHV8 infection in certain African regions, where endemic KS has been reported, is reported to have reached rates of 60% and higher [2,57,110,[121][122][123][124]. Human herpesvirus 8 genotypes isolated from KS patients from South Texas exhibit a distinct distribution pattern from those in other areas in the US, suggesting that HHV8 might have a different epidemiology in this region [125].
Most evidence indicates that sexual contact, particularly among homosexual men, is the primary route of HHV8 transmission in North America and Europe [2,22,109,121,126,127]. Initial studies among children in these geographic regions indicated that HHV8 infection was rare or nonexistent, with prevalence of 0% reported among HIV-infected children from the United States [128] and among HIV-seronegative children from the UK [21].

Confirmed manifestations
Primary infection Acute febrile illness with a rash Cancer Kaposi sarcoma Primary effusion lymphoma, which is also known as body cavity-based lymphoma; a specific type of non-Hodgkin lymphoma Multicentric Castleman Disease

Possible association
Multiple myeloma ported among virginal and monogamous women in Sweden [137]. An epidemiologic study of a French Guiana village identified statistically significant mother-child and sibling-sibling correlations of HHV8 infection, suggesting intrafamily spread of HHV8 [138]. A study in Johannesburg, South Africa, found that children born to HHV8 seropositive mothers exhibited a statistically significant increase in HHV8 seroprevalence compared with children of seronegative mothers, with 30% seroprevalence among children younger than 10 years of age born to seropositive mothers [139]. Thus, there appears to be appreciable nonsexual transmission of HHV8. Virus excretion in saliva and saliva exchange is probably a major means of horizontal and intrafamily HHV8 transmission [138,140-

Clinical manifestations of primary HHV8 infection
Primary HHV8 infection in immunocompetent children was characterized in a report of 8 children who were identified from among 86 children evaluated for a febrile illness of undetermined origin [142••]. The fever persisted for a mean of 10 days (range 2-14 days). A maculopapular skin rash occurred in 5 of 6 children, with a mean duration of 6 days (range 3-8 days

Conclusion
There is increasing awareness of the prevalence of HHV8 infection and recognition of the role of horizontal transmission of HHV8 virus among children. There are significant differences in HHV8 prevalence between adult populations and, it now appears, also children from different geographic regions and socioeconomic groups. Intra-family spread, primarily through saliva, may be the primary means of nonsexual HHV8 transmission and the primary mode of spread among children. The ramifications of horizontal spread of HHV8 among family members and potential for wider spread among larger populations remain to be determined.