KSHV Latency in Transformed B-cells: The Role of LANA1 as a Therapeutic Target

Abstract

Kaposi’s sarcoma (KS) was originally described in 1872 by the Hungarian dermatologist Moritz Kaposi as an idiopathic, multiple pigmented sarcoma of the skin. This type of KS, later classifi ed as classic KS, predominantly occurred in elderly people, particularly men of Mediterranean, Eastern European, or Jewish descent. A high occurrence of African or endemic KS was reported during the early 1950’s in equatorial African countries, while during the 1960’s KS emerged among immune-suppressed patients following organ transplantation. A tremendous increase in the incidence of KS was noticed during the early 1980’s in parallel with the acquired immunodefi ciency syndrome (AIDS) epidemic, leading to a formal recognition of KS as an AIDS-associated malignancy. The geographic variations in the incidence of KS together with the relatively high occurrence of AIDS-KS, particularly among homosexual men, suggested the existence of a unique KS infectious agent (7, 8). In 1994 Chang and colleagues, amplifi ed two novel DNA sequences from an AIDS-associated KS lesion, by using a subtractive hybridization technique (representational difference analysis (RDA)). These sequences displayed homology to herpesviral capsid and tegument genes and led to the complete sequencing of the 165 Kbp viral genome of the newly discovered virus, Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) or human herpesvirus 8 (HHV-8). KSHV was established as being present in virtually all pathologically confi rmed KS specimens (11, 12). Treatment with highly active antiretroviral therapy (HAART) has been associated with a dramatic decline in the incidence of KS (31), so that AIDS-associated KS is uncommon overall in the Western world. Sub-Saharan Africa has the highest rates of infection (due mostly to the high rates of AIDS) with many countries experiencing sera-prevalence rates exceeding 60%, so that in certain African countries it is now the most common cancer in adult men, and the second most common in adult women (44). The incidence of KS among transplant recipients is proportional to the ethno-geographical prevalence of KSHV, ranging from 0.5% in most Western countries to 5.3% in Saudi Arabia (50). In addition to KS, which is a tumour of endothelial cell origin, several haematological predominantly B cell disorders are also associated with KSHV. The two most well characterized are AIDS-associated primary effusion lymphomas (PEL) and a subset of multicentric Castleman’s disease (MCD), an aggressive lymphoproliferative disorder. PELs are monoclonal, non-Hodgkin’s B cell lymphomas that are commonly co-infected with EBV. Cell lines established from PEL, unlike KS tumour explants, stably maintain viral episomes at high copy number (30–150 copies per cell) and are the source of virus for most virologic and serologic studies. Most studies on latency of gammaherpesviruses (EBV) used lymphoblastoid cell lines that were derived from lymphomas or were established by in vitro infection/immortalization of peripheral blood lymphocytes. In vitro immortalized cells lines can be cultured indefi nitely. PEL cell lines that carry latent KSHV have been successfully established, although no in vitro immortalization of B lymphocytes has been reported yet (10, 44). KSHV viral genome consists of a ∼140kb long unique coding region fl anked by a multiple GC rich ∼800bp TRs (terminal repeats) giving a total estimated size of around 170kb (57, 60). In analogy