AEGiS-Glasgow [PL9.2] Kaposi sarcoma herpesvirus: update

Seventh International Congress on Drug Therapy in HIV Infection

Glasgow, UK - 14-17 November 2004

[PL9.2] Kaposi sarcoma herpesvirus: update

Int Cong Drug Therapy HIV 2004 Nov 14-18;7:Abstract No. PL9.2

Chris Boshoff , Cancer Research UK Viral Oncology Group
Wolfson Institute for Biomedical Research, University College, London, UK

The incidence of HIV-related cancer before and during the ART era indicates that oncogenic viruses continue to contribute to the majority of these cancers and they are therefore considered opportunistic malignancies. ART has lead to a definitive decline in the incidence of certain AIDS-defining cancers including Kaposi sarcoma (KS) and non-Hodgkin's lymphoma. Before ART, non-AIDS-related malignancies accounted for <1% of all causes of death in this population, this has now raised to over 25% because of the sharp decline of competitive risks, the relative frequent co-infection in this population with the oncogenic viruses Hepatitis B or C, the aging of the HIV-infected population and the possible direct contribution to oncogenesis by HIV-1 or ART.

Kaposi sarcoma (KS) is the most common neoplasm in HIV-1 infected individuals and in certain countries, the most common tumor after an organ transplant. Due to the HIV-pandemic, KS is also one of the most common tumors overall in sub-Saharan Africa. Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) is essential in the etiopathogenesis of KS. In the vast majority of infected individuals KSHV persists without harm to its host. When the balance between pathogen and host immunity is disturbed, due to HIV infection or iatrogenic immunosuppression, KSHV reactivation and outgrowth of KSHV infected cells occur. Other tumors associated with this pathogen include multicentric Castleman's disease and primary effusion lymphoma.

KS is a tumor of cells differentiating towards lymphatic endothelial cells (LECs). LECs are permissive to infection by KSHV and to morphological transformation by this pathogen. The expression profile of infected LECs reveals that this pathogen induces genes associated with cell attachment, migration and differentiation. KSHV also induces an array of cytokines and their receptors, including PDGFA, B and PDGFRalpha, endothelin-1 and angiopoietin-2. ELISA confirms significant upregulation of angiopoietin-2 in the supernatant from infected LECs. Individuals with KS have significantly higher plasma levels of angiopoietin-2 and the lymphangiogenic molecule VEGFD, but not the angiogenic molecule VEGFA. Furthermore, plasma VEGFD and angiopoietin-2 levels decrease during KS resolution. These data infer that KS is a tumor of the lymphatic endothelial lineage and lymphangiogenic molecules are involved in its pathogenesis. KSHV-infected LECs provide an experimental model to study Kaposi sarcomagenesis and KS should provide a model to test anti-lymphangiogenic therapeutics.

SESSION 9: HIV-RELATED INFECTIONS, CO-INFECTIONS AND MALIGNANCIES
2004-11-14
PL9.2

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