Reactivation and role of HHV-8 in Kaposi's sarcoma initiation.
Kaposi's sarcoma (KS) is an angioproliferative disease occurring in several clinical-epidemio-logic forms but all associated with infection by the human herpesvirus-8 (HHV-8). At least in early stages, KS is a reactive disease associated with a state of immune dysregulation characterized by CD8+ T-cell activation and production of Th1-type inflammatory cytokines (IC) that precedes lesion development. In fact, evidence indicates that IC can trigger lesion formation by inducing the activation of endothelial cells that leads to adhesion and tissue extravasation of lymphomonocytes, spindle cell formation, and angiogenesis, and HHV-8 reactivation that, in turn, leads to virus spread to all circulating cell types and virus dissemination into tissues. Due to virus escape mechanisms and deficient immune responses toward HHV-8, virus reactivation and spread are not controlled by the immune system but induce immune responses that may paradoxically exacerbate the reactive process. The virus is recruited into "activated" tissue sites where it finds an optimal environment for growth. In fact, viral load is very low in early lesions, whereas almost all spindle cells are infected in late-stage lesions. Although early KS is a reactive process of polyclonal nature that can regress, in time and in the presence of immunodeficiency, it can progress to a true sarcoma. This is likely due to the long-lasting expression of HHV-8 latency genes in spindle cells associated with the deregulated expression of oncogenes and oncosuppressor genes and, for AIDS-KS, with the effects of the HIV-1 Tat protein.
Ensoli
B
B
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy. ensoli@iss.it
Stürzl
M
M
Monini
P
P
D016207:Cytokines / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D015696:Gene Products, tat / Q000096:biosynthesis; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000821:virology; D012307:Risk Factors; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000821:virology*
D016207:Cytokines; D015696:Gene Products, tat