Research into Kaposi Sarcoma and KS Herpesvirus
Background
IIB's 20th century cohort studies of high risk populations and its analyses of Surveillance, Epidemiology and End Results (SEER) data provided compelling evidence that Kaposi sarcoma (KS) was caused by a sexually transmissible virus. Chang, et al. discovered the KS-associated herpesvirus [KSHV, also known as human herpesvirus 8 (HHV-8)] in 1994. Subsequently, IIB's program yielded much of the global knowledge on KSHV and its relationship to KS. To improve the overall field, IIB worked intensively to develop sensitive, specific, and high-throughput serologic and molecular KSHV assays. With these assays, in recent years IIB discovered pockets of KSHV micro-endemicity as well as large differences in seroprevalence among populations, a previously unknown KSHV genotype (F) in isolated Amazonian and African rainforest peoples, and evidence that KSHV is transmitted not only by routine contact, probably with saliva, but also by sexual and blood-borne exposures.
Classical KS and KSHV
Collection of specimens and data for a population-based case-control study conducted throughout Sicily was completed in FY2006 and will be analyzed in FY2007. The hypotheses address the effects of smoking; skin diseases and their treatments; exposures to soil, plants, and water; and variants in immunity- and inflammation-related genes on the risk of KSHV infection, classical KS among those infected, and KSHV salivary shedding and viral load. To increase statistical power for genetic polymorphism analyses, in FY2007 dried blood spots will be collected from a large clinic population of classical KS patients in Milan, who will be compared to a matched sample of population-based controls from a lung cancer study recently completed in the Milan region by the DCEG Genetic Epidemiology Branch. Genetic analyses will continue into FY2008.
KSHV Coinfections and Water Exposure
KSHV infection is common in Africa, but its distribution varies widely. Based partially on completed IIB projects in Uganda and Egypt, we postulate that KSHV distribution is modulated, in part, by environmental factors, such as parasitic infections that modify the risk of acquisition or transmission. KSHV seroprevalence and KS risk are high in Uganda, but as elsewhere their distribution is heterogeneous. The Branch has received preliminary approval to test blood samples from the Uganda National HIV Sero-Behavioral Survey (UHSBS; 2004/2005) to investigate environmental (parasitic infections, source of drinking water, highland vs. lowland) and socioeconomic factors (urban vs. rural, education, income, occupation) postulated to be associated with KSHV seropositivity and with KSHV DNA detection and level in blood cells. Additional analyses are planned to uncover associations of KSHV seropositivity with previously collected questionnaire data on sexual activity and diseases (HIV, syphilis, and HSV2 serology) among adults in this predominantly heterosexual population. Using data from the cancer registry in Uganda, we plan to estimate the risk of KS given KSHV seropositivity, as we did previously for the Mediterranean region.
KS Molecular Studies
IIB and its laboratory collaborators are addressing unresolved questions on the genomic integrity of KS and whether multiple tumors in individuals are clonal. Identifying clonal abnormalities in tumors would confirm its malignant nature and clarify its pathogenesis. To determine genomic integrity (loss or gain of gene regions) and clonality of KS, in FY2007 we plan to complete analyses using digital comparative genomic hybridization and other clonal markers to compare multiple tumors with each other and with normal skin from 80 Ugandan subjects with AIDS-related and endemic KS. To investigate the possibility of donor transmission of KS cells, which would corroborate a study of Italian transplant recipients, in FY2007 we expect to receive KS tumor specimens from African transplant recipients. Analyses of these will be completed by FY2008.
