Crazy 8: unraveling human herpesvirus 8 seroprevalence.

Received 21 June 2004; accepted 23 June 2004; electronically published 13 September 2004. Reprints or correspondence: Dr. S. David Hudnall, Dept. of Pathology and Laboratory Medicine, University of Texas Medical Branch, 301 University Blvd., Galveston, Texas 775550741 (shudnall@utmb.edu). Clinical Infectious Diseases 2004; 39:1059–61 2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2004/3907-0025$15.00 The eighth and most recently discovered human herpesvirus was first detected in proliferating lymphatic endothelial cells of the skin tumor known as Kaposi sarcoma (KS) [1]. Since then, this virus, which is now known both as human herpesvirus 8 (HHV-8) and KS-related herpesvirus (KSHV), has been detected in a number of other sites, including malignant B cells of AIDS-associated primary effusion lymphoma (PEL), occasional large B cells in the plasma cell variant of Castleman disease, peripheral blood B cells and monocytes in patients with KS, and saliva specimens obtained from patients with AIDS [2–7]. Unlike most infectious agents, herpesviruses maintain an asymptomatic persistent latent infection in the host following primary infection. Lifelong persistence of virus is accompanied by lifelong persistence of both humoral and cellular antiviral immunity. Serologic detection of herpesvirus antibodies has proved to be of immense value not only in the diagnosis of primary infection, but also for determination of the prevalence of infection in various population groups. The high rates of adult seropositivity reported from various regions of the world indicate that most herpesvirus infections are highly prevalent and not geographically restricted. In an early landmark study, Lennette et al. [8], using an indirect immunofluorescence assay (IFA) for detection of both latent and lytic viral antigens, reported HHV-8 seroprevalence in the general adult population from the San Francisco area of ∼25%. In contrast, other early studies of HHV-8 seroprevalence that used an IFA for detection of antibody to latency-associated nuclear antigen (LANA) indicated that infection was highly restricted to a few specific groups at high risk for development of KS, such as HIVinfected homosexual males and adults from regions of KS endemicity [9–11]. Although the theory that HHV-8 infection is sexually transmitted was consistent with the high seropositivity noted in homosexual males, it was inconsistent with the high seropositivity in older heterosexual Mediterranean men and young African children. Evidence in support of an oral route of transmission was subsequently provided by studies in which saliva specimens obtained from patients with AIDS were shown to contain HHV-8 [6, 7]. Although these findings provided an alternative mechanism for virus spread in groups other than homosexual males, the low seroprevalence in regions of the world in which KS is not endemic reported in early studies that used the LANA assay was puzzling. One explanation that was offered was that HHV-8 had only recently spread to regions of nonendemicity via the HIV epidemic. However, because all other human herpesviruses are ubiquitous in their worldwide distribution, this explanation was not entirely convincing. Determination of viral seroprevalence is highly dependent on the characteristics of the assay that is used. Great care must be taken to select an assay that is not only highly specific but also highly sensitive. High sensitivity is particularly important when the assay is used to determine seroprevalence in healthy populations in which antibody titers from past exposure may be quite low. HHV-8 serological analysis was originally performed with an antiLANA IFA by means of AIDS-associated PEL cell lines that were latently infected with HHV-8 and adapted to cell culture [9–11]. The LANA assay revealed an HHV-8 seroprevalence of 2%–27% (median, 10%) in 6 studies of adult blood