Viral and Cellular Cytokines as Therapeutic Targets in AIDS-Related Lymphoproliferative Disorders

Since the advent of highly active antiretroviral therapy (HAART) and its widespread use, the incidence of AIDS-defining illnesses has decreased dramatically, leading to a much longer survival of patients. Despite some exciting new leads, non- Hodgkin's lymphoma (NHL) remains a fatal malignancy for the vast majority of patients with acquired immunodeficiency syndrome (AIDS). Multiple molecular pathways appear to operate in AIDS lymphomagenesis and some may preferentially be associated with specific malignant histopathologic categories or anatomic sites of origin. AIDS-associated lymphomas share several features, including B-cell lineage derivation, diffuse aggressive histology, and frequent origin from or involvement of extranodal sites. Recently, high-grade primary effusion lymphomas (PEL) have been reported in patients with advanced AIDS. PEL is recognized as a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8). KSHV genes are likely to contribute to the neoplastic phenotype of PEL cells that require cytokines and factors from the host or encoded by the virus for growth in vivo. KSHV is also thought to dramatically affect the incidence, type, and course of multicentric Castleman's disease, another lymphoproliferative disorder over-represented in patients with AIDS. This review summarizes the current knowledge of autocrine growth factor loops and angiogenic factors that are involved in the pathogenesis of KSHV-related lymphoproliferative disorders in AIDS. Deregulated cytokines may represent potential targets of novel therapeutic strategies.