Kaposi's sarcoma is a multifocal malignancy observed in elderly Mediterranean men (so-called Classic Kaposi's sarcoma), individuals in Africa (endemic Kaposi's sarcoma) and patients with immune disorders, including those undergoing organ transplantation (iatrogenic Kaposi's sarcoma) or infected with HIV (epidemic Kaposi's sarcoma). In all of these four clinical categories of Kaposi's sarcoma, the tumour represents aberrant angiogenesis or lymphangiogenesis (i.e. formation of new blood or lymphatic vessels, respectively ) through proliferation of spindle-shaped endothelial cells that line these vascular structures.
Overwhelming molecular and serological evidence has now accrued to qualify Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus (HHV)-8, as the causal agent of the four clinical forms of Kaposi's sarcoma (see ). This virus was discovered in 1994 by Chang et al. , in Kaposi's sarcoma lesions where it infects the spindle cells  (see Fig. 1). At late stages of Kaposi's sarcoma, all spindle cells are infected with the virus , with low levels of lytic replication demonstrable . KSHV is also associated with the pathogenesis of primary effusion lymphoma (PEL, a rare B-cell lymphoma)  and multicentric Castleman's disease (MCD) , both principally affecting AIDS patients. Its involvement in other diseases is more controversial.
In issue 10 of AIDS, Lanternier et al. describe a cohort of 28 young, HIV-negative homosexual men with Kaposi's sarcoma. This occurrence is not a new observation as there are multiple anecdotal cases and reports of small numbers of such subjects, but the size of this cohort raises the profile of the study and enabled the authors to analyse the subjects in more detail. Does this cohort represent a fifth clinico-epidemiologic form of Kaposi's sarcoma? Unlikely, since such a significant interpretation would require compelling data that the Kaposi's sarcoma they describe differs from the four clinical forms currently recognized, for example in pathology and location of lesions. Alternatively, the cofactors predisposing these subjects to develop Kaposi's sarcoma need to be identified. Lanternier et al. resolved neither requirement unequivocally, but the Kaposi's sarcoma in their cohort resembled Classic Kaposi's sarcoma: it occurred on the lower limbs and lacked visceral involvement. However, it developed 10–20 years earlier than expected for Classic Kaposi's sarcoma. Why do these younger gay men develop this Kaposi's sarcoma?
Like other oncogenic human viruses, genetic, behavioural or environmental cofactors are likely to be important in the manifestation of KSHV disease (Table 1) [10–17]. HIV is one such cofactor, at least in part because of its impact on the immune system that itself functions as an important cofactor in Kaposi's sarcoma development. In organ transplant recipients undergoing iatrogenic immunosuppressive therapy to prevent graft versus host disease, Kaposi's sarcoma can regress spontaneously upon withdrawal of the immunosuppressive therapy. Likewise, highly active antiretroviral therapy (HAART) for HIV infection restores immune function and reduces Kaposi's sarcoma incidence . Given the positive correlation between KSHV replication and Kaposi's sarcoma development [18–20], and that Kaposi's sarcoma is frequently associated with immune compromise, is KSHV therefore effete, lacking in vigour? Is immune suppression a prerequisite for KSHV replication and concomitant disease manifestation?
Lanternier et al.'s study suggests that is not the case, as do at least two other lines of evidence. First, approximately one quarter of the KSHV genome encodes a veritable panoply of immune modulatory proteins . Given that viral genomes are parsimonious, why would evolutionary pressure sustain such a diversity of immunomodulatory activities if they were not required to defend against robust immune responses capable of eliminating infected cells, not those of an immune compromised individual? Establishment of KSHV latency in vitro occurs with low efficiency and is dependent upon epigenetic factors such as modification of the chromatin structure . Thus, continuous rounds of lytic infection in vivo may be required in order to recruit additional latently infected cells, which would otherwise decline as KSHV episomes are lost upon cell division. Lytic replication is also necessary for the initial establishment of infection and dissemination in the host. This dependence on lytic replication could explain the retention of the diversity of immunomodulatory activities, particularly in Kaposi's sarcoma lesions themselves, which are infiltrated with abundant leukocytes, including interferon-γ-producing cells (for further discussion, see ).
Second, although HIV-infected subjects with Kaposi's sarcoma typically have low CD4+ T-cell counts, a recent study  describes a cluster of HIV-positive, Kaposi's sarcoma-positive individuals with normal CD4+ T-cell counts. A low CD4+ T-cell count (and KSHV infection) is not therefore mandatory for the development of Kaposi's sarcoma. In some regions, such as Alexandria, Egypt, remote areas of Amazonia and Papua New Guinea and also in parts of China, KSHV prevalence is high yet the occurrence of Kaposi's sarcoma is low (reviewed in ). Conversely, equatorial African countries, where malaria is endemic, and certain Mediterranean countries have a higher incidence of Kaposi's sarcoma (reviewed in ).
These observations reinforce the cofactor theory, which brings us back to the discussion of why the subjects in the Lanternier study develop Kaposi's sarcoma. What cofactors are at work in these HIV-negative subjects? They lacked overt immune deficiency, though more subtle immune deficiencies  or dysfunctions cannot be excluded. Indeed, immune hyperactivity may stimulate Kaposi's sarcoma tumourigenesis as suggested by Levy and Ziegler over a decade before the discovery of KSHV , and this mechanism could account for Kaposi's sarcoma development when CD4+ cell counts are being restored . Perhaps the Lanternier et al.  study subjects have a chronic underlying genetic or other causal immune dysfunction that stimulated KSHV replication and concomitant Kaposi's sarcoma development?
Equally, otherwise healthy KSHV-infected subjects may have a genetic or ethnic predisposition to developing Kaposi's sarcoma. HLA polymorphism may be important (Table 1). Many of the Lanternier subjects had travelled in countries with endemic or Classic Kaposi's sarcoma, in which the seroprevalence of KSHV is high; they might have been infected with a different, more pathogenic subtype of KSHV, but differential pathogenicity of KSHV subtypes remains controversial . Other cofactors in Kaposi's sarcoma development include age, the recreational use of stimulant amyl nitrites (Table 1) and sex.
In regard to sex, KSHV prevalence is disproportionately high in homosexual men. Although KSHV is more commonly found in saliva than semen [29,30], transmission has yet to be associated with a specific homosexual practice, but does correlate with the number of lifetime sexual partners [31,32]. The seroprevalence of KSHV in heterosexual men and women is similar , suggesting heterosexual transmission is inefficient , but Kaposi's sarcoma is more common in males . This sex bias is perplexing, but hormonal cofactors could be at work. In this regard, human chorionic gonadotrophin (hCG), the pregnancy hormone, has attributed anti-Kaposi's sarcoma activity in vivo with apparent physiological justification from in-vitro studies . However, the presence of contaminants in commercial hCG preparations confounds these observations , aside from determining with certainty whether KSHV replication and/or Kaposi's sarcoma development is influenced by sex hormones.
In conclusion, the most appropriate clinico-epidemiologic classification for the subjects in the Lanternier study is ‘Classic Kaposi's sarcoma’, unless there are in the future certain risk factors (Table 1) that would place them in a separate category. KSHV causes Kaposi's sarcoma, but, if immune deficiency is not the only other risk factor associated with Kaposi's sarcoma development, what are the identities and significance of the others?
Research in D.J.B.'s laboratory is currently funded by Cancer Research UK and the Medical Research Council.
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