Human herpesvirus 8 latent-state gene expression and apoptosis in Kaposi's sarcoma lesions.

The evidence that Kaposi’s sarcoma (KS)-associated herpesvirus (also known as human herpesvirus 8 [HHV8]) is the primary etiologic agent of KS in both acquired immunodeficiency syndrome (AIDS) and non-AIDS situations has been accumulating rapidly. Two recent articles, one by Dupin et al. (1) and the other by Sturzl et al. (2), which appears in this issue of the Journal, provide the most compelling evidence yet for the almost universal presence of HHV8 and its latent-state gene products in the spindle-like tumor cells characteristic of late-stage angiogenic nodular KS lesions. Although previously known as only a very rare skin condition occurring primarily in elderly Mediterranean Jewish men (classical KS) and in adolescent males in the malaria belt in central Africa (endemic KS), KS has come to sudden prominence since the early 1980s in the United States as one of the original defining conditions of the AIDS epidemic in young homosexual men. The incidence of KS is now recognized to be increased more than 20 000-fold in homosexual AIDS patients and more than 500-fold in solid organ transplant patients (iatrogenic KS) relative to ethnically matched control subjects, and KS has become the most frequently encountered tumor in some sub-Saharan African countries. In 1990, Beral et al. (3) predicted that AIDS-associated KS was caused by a second infectious agent transmitted independently of human immunodeficiency virus type 1 (HIV-1), and Chang et al. (4) in 1994 identified a novel herpesvirus genome related to Epstein-Barr virus (EBV) within KS lesions. Subsequently, the 80 or so genes of this virus were mapped and characterized in record time (5–9). Footprints of the virus have been found by DNA polymerase chain reaction (PCR) assays in virtually all KS lesions as well as in several AIDS-associated lymphoid tumors (known as pleural effusion lymphoma [PEL] and multicentric Castleman’s disease), and high-quality serologic reagents are now available to detect infected individuals. It is not in the best interests of a virus to cause lethal tumors in its natural host, but the evidence from recent strain variability analysis (10) clearly suggests that HHV8 is an ancient human virus and is not a recently acquired pathogen. However, the gammaherpesvirus group to which HHV8 belongs has evolved mechanisms to immortalize the infected cells so that they continue to proliferate while the viruses maintain a long-term quiescent or latent state with minimal viral gene expression to provoke host immune responses. This scenario provides a reservoir for the virus to persist and from where it must also have a route to periodically reactivate and escape to infect a new host. Skepticism has been expressed from some quarters that a ubiquitous lytic herpesvirus could not provoke tumor growth, and it may just be a passenger virus brought to the site accidentally by infiltrating inflammatory cells or that HIV-1 must be the real culprit (11). However, unexpected but important discoveries that HHV8 encodes a series of novel genes (5–9) give credence to the tumorigenic properties of HHV8. The genes include viral homologues of cellular interleukin 6 (IL-6), macrophage inflammatory protein 1 (MIP-1), Bcl-2, and interferon regulatory factors (IRFs) (5–9) as well as a cyclin-D (cyc-D) homologue, an alpha chemokine G-protein-coupled receptor (GCR) encoded by open reading frame (ORF)-74, and tyrosine kinase-signaling membrane proteins encoded by ORF-K1 and ORF-K15. Furthermore, several of these proteins have constitutive in vitro transforming and even angiogenic properties (12–15). Unlike its cousin EBV, which is ubiquitous in all human populations, HHV8 seropositivity (as a measure of current or previous infection) is rare in the general population (probably no more than 1% in the United States), except in those countries that have relatively high levels of classic or endemic KS. However, HHV8 seropositivity rates in homosexual males are as high as 50%, and they are up to 85% in AIDS patients (16,17). The increased rates of KS in homosexual AIDS patients are probably attributable to a combination of higher rates of infection by HHV8 in that population, as well as to CD4 depletion and immunosuppression and possible direct enhancing effects of HIV-1 itself; in contrast, in sub-Saharan Africa, where HHV8 was already prevalent, the huge increase in KS incidence is attributable to the rapid spread of HIV-1. Infection with HHV8 does not by itself introduce a high risk of contracting KS, although it is now almost certain that no cases of KS occur without the presence of HHV8 as the primary triggering etiologic agent. However, for those AIDS patients infected with both viruses, the chance of developing KS within 10 years may be as high as 50%. Obviously, for a virus of this type that cannot yet be grown efficiently in cell culture and is very unlikely to be transmissible into animal models, classical Koch’s postulates cannot be fulfilled. However, apparently infectious virus can be recovered from filtered supernatants derived from TPA (phorbol 12myristate 13-acetate)-treated PEL cell lines and gives rise to latently infected, proliferating, spindle-shaped cells in primary human endothelial cell cultures (18,19). The PEL cell lines themselves and even NIH/3T3 cells transformed in vitro by the vGCR gene of the virus give rise to highly angiogenic tumors in nude mice (12,13). One drawback has been that spindle cell lines established from KS tumors themselves fail to retain the virus. Perhaps the virus reactivates and kills those cells that carry it, or the surviving cells that grow out have mutations that bypass the need for the virus to maintain the production of vascular endo-