Seroepidemiology

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Serologic Assays

Several HHV-8 serologic assays are currently available. The most widely used assays are based on detection of latent or lytic antigens in HHV-8-infected PEL cell lines, either by immunofluorescence (110-112) or enzyme immunoassay (113). Assays also have been described that detect antibodies to recombinant HHV-8 latent and lytic proteins or synthetic peptides. Lytic proteins shown to be immunogenic include ORF (open reading frame) 65 (112), ORF 26 (114), and ORF K8.1 (115,116). The only latent antigen thus far to be used in recombinant assays is ORF 73, which is the same antigen detected in latent immunofluorescence assays (59,117,118). A study comparing various assays including recombinant proteins (ORFs 65 and K8.1) and immunofluorescence assays concluded that immunofluorescence assay (IFA) followed by confirmation with Western blot reactions with a panel of latent and lytic immunogenic antigens provide a reliable, sensitive, and specific method to detect HHV-8 antibodies (119).

Seroprevalence

Northern Europe and North America

The seroprevalence of HHV-8 in the different HIV risk groups correlates with the incidence of KS. In Northern Europe and North America, HHV-8 is found predominantly in HIV-positive homosexual men (110-112,120,121) and not in HIV-positive patients with hemophilia, drug users, or heterosexuals.

In a cohort of men in San Francisco, it was shown that HHV-8 infection is associated with the number of homosexual partners and correlates with a previous history of a sexually transmitted disease (STD, such as gonorrhoea) and HIV infection (122), suggesting that HHV-8 is sexually transmitted. In homosexual men attending the STD clinic at St. Thomas Hospital in London, in univariate analysis HHV-8 prevalence was correlated with a history of sex with an American, suggesting that HHV-8 was perhaps first introduced into the homosexual communities in the epicenters of HIV in the United States before spreading to Europe (123). At the moment we can conclude that HHV-8 is transmitted among homosexual men during sex, although this does not necessarily imply sexual transmission.

Mediterranean Europe

The incidence of classic KS is significantly higher in Italy than in the United Kingdom or the United States (3,124). Similarly, the prevalence of antibodies to HHV-8 in blood donors in Italy is significantly higher than rates reported in the United Kingdom or the United States (125,126). Furthermore, the incidence of classic KS in Italy shows considerable regional variation (124) and the prevalence of HHV-8 in different regions correlates with this (125,127). In addition, the geometric mean titer of anti-HHV-8 antibodies is highest in blood donors from the south, where the incidence of KS and the prevalence of HHV-8 is highest (125). This is reminiscent of EBV infection, in which a high anti-EBV antibody titer correlates with an increased risk of developing Burkitt's lymphoma or nasopharyngeal carcinoma (128,129).

Israel

The incidence of classic KS in Israel is among the highest in the world (130). Similarly, the seroprevalence of HHV-8 among Israeli Jews is higher than that seen in the general populations of Western Europe and North America (131). The incidence of classic KS is higher among North African (Sephardic) Jews than those of European descent (Ashkenazi), and the seroprevalence of HHV-8 among the different Jewish groups correlates with this (131). Furthermore, mother-to-child transmission is important in the acquisition of HHV-8 in Israel (131).

Africa

Endemic KS existed in Africa long before the AIDS epidemic; however, AIDS-KS is now one of the most common tumors in many parts of Africa. In Africa, where KS rates are relatively high among HIV-positive individuals, the prevalence of antibodies to HHV-8 is also higher than in North America and Northern Europe (112,132-135). Early acquisition of HHV-8 in Africa is likely because KS is seen in African children (7). Indeed, the prevalence of antibodies to HHV-8 increases steadily with age in Africa (Fig. 6) (134,135), and this occurs even before puberty (136-139). This indicates that HHV-8 is not predominantly transmitted during sex, as is seen among homosexual men in the West. Mother-to-child transmission and sibling-to-sibling transmission has been shown to occur in South Africa and in a Noir-Marron population living in French Guyana (136,140). About one third of HHV-8 positive black mothers in South Africa transmit the virus to their children (136). Interestingly, in contrast to mother-to-child transmission, father-to-child transmission does not appear to occur among the Noir-Marron population tested. In South Africa there is a significantly lower prevalence of anti-HHV-8 antibodies among whites that among blacks, and in black cancer patients the seroprevalence of HHV-8 declines with increasing education, suggesting that factors associated with poverty may contribute to the transmission of the virus (135).

Transmission

Although one group reported the frequent detection of HHV-8 in the semen of healthy Italian donors (141), in North America and the United Kingdom the current consensus is that HHV-8 is present only intermittently in the semen of patients with KS and sometimes in HIV-positive patients without KS, but only rarely in semen donors (142-147). HIV-8 has also been found in prostate biopsies of HIV-positive men with or without KS (148). HHV-8 shedding into semen from prostate fluid is therefore a possible mode of transmission. Infectious virus is also found in the saliva of HIV-positive individuals (149). In patients with classic KS, HHV-8 DNA was shown to be present in tonsillar swabs and in saliva (126). Although studies in homosexual men indicate that HHV-8 is transmitted during sex and the risk of having HHV-8 increases with the number of sexual partners, the exact mode and route are not known. Semen and saliva are possible routes of viral transmission, but their respective contribution to infection is still unknown. The role of breast milk, saliva, and other horizontal routes for mother-to-child and sibling-to-sibling transmission is also still unknown.

Fig. 6. Age-specific seroprevalence of HHV-8 and HIV in black South African patients with cancer. (From ref. 135 with permission.)

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