Frederick National Laboratory for Cancer Research
Building 535, Suite 412
Frederick, MD 21702-1201
Denise Whitby received her PhD from the Institute of Cancer Research, University
of London, UK. She joined the AIDS Vaccine Program in 1999 where she is head of
the Viral Oncology Section. She has served as a member of the steering committee
for the European mulitcentric case control study on the causes of lymphoma (EPILYMPH)
since 1998 and serves as co-chair of the infectious agents sub-group of Interlymph,
an international consortium of case control studies on lymphoma. In February 2009
Denise participated in an International Agency for Research on Cancer (IARC) working
group on biological agents for volume 100 of the IARC Monographs on the evaluation
of carcinogenic risks to humans in Lyon, France.
Mission: "Understanding the role of viruses in cancer – Especially in the context of AIDS"
The overall aim of the Viral Oncology Section is to study the role of viruses in cancer. Our studies are focused mainly on Kaposi’s sarcoma-associated herpesvirus (KSHV) and related malignancies. Our approach to research encompasses epidemiology, molecular virology, immunology and translational studies. To achieve our research goals we have developed an extensive network of collaborations with investigators throughout the US and internationally. We have developed research projects with investigators in Uganda, Cameroon, Kenya, South Africa and elsewhere that have resulted in important capacity building in terms of providing training for local investigators as well as technology transfer.
KSHV is a gammaherpesvirus discovered in 1994 that causes Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Kaposi’s sarcoma is a notable AIDS associated cancer which can also occurs in HIV negative subjects. KSHV has a distinct geographic distribution, being very prevalent in sub-Saharan Africa, relatively common in areas of the Mediterranean and rare elsewhere, except for specific ethnic groups and men who have sex with men.
Our current research is grouped into three main project areas:
Project 1: KSHV Epidemiology and Transmission
We are investigating how epidemiology of KSHV is evolving as the HIV epidemics changes. We are currently focusing on three established longitudinal cohorts: the Ugandan General Population Cohort (GPC) in rural Uganda, the AIDS Clinical Trials Group sponsored ACTG Longitudinal Linked Randomized Trials Cohort (ALLRT) and the Multicenter AIDS Cohort (MACS). We are also investigating environmental risk factors for KSHV transmission, acquisition and associated diseases. In a longitudinal mother-child cohort in Uganda we found that, in addition to HIV malaria and hookworm infections were risk factor for KSHV seropositivity, we are now investigating how these co-infections might affect viral replication and shedding; currently we are collaborating to similarly study an analogous Kenyan cohort. Furthermore, we have found in a KS case control study in Cameroon that, in addition to lack of insect nets, the use of traditional healing practices was associated with KS risk. This finding corroborates our previous in vitro studies on the potent activity of certain African natural products on viral reactivation.
Project 2: KSHV Immunity and Pathogenesis
To investigate the range of immune responses to KSHV and its association with transmission, disease risk and progression we performed a systematic study of the KSHV proteome, utilizing recombinant proteins from each viral ORF. We tested these by ELISA in subjects with KSHV related disease and healthy donors, demonstrated that the humoral immune response to KSHV is highly heterogeneous in both breadth and depth. We have identified new antigens and developed a flexible multiplexed bead-based assay. We are now utilizing this tool for KSHV epidemiology and to understand if specific responses are associated with risk of KSHV transmission or disease. We have developed tools to investigate the role of microRNA in the pathogenesis of KSHV related diseases and we are currently characterizing KSHV infected cells in infected subjects as well as developing model systems for B cell infection in vitro
Project 3: Viral and Host Genetics in KSHV Infection and Disease
We are investigating the potential role of genetic variation in this in a panel of human genes involved in virus cell interactions and antiviral immune response in Cameroonian subjects. Furthermore, we are collaborating with domestic and international investigators to perform genome wide association studies. Viral genetic diversity is also an understudied topic with potential pathogenetic significance, which we are investigating. We described for the first time polymorphisms in virally encoded microRNAs, showing their association with disease risk, and we are continuing to characterize miRNAs sequences ex vivo and their function in vitro. We are now studying variations in the entire viral genome in lab strains and clinical samples using NGS approaches.