Photo of Dr. Whitby

Denise Whitby, Ph.D.

Viral Oncology Section

Leidos Biomedical Research, Inc.
Frederick National Laboratory for Cancer Research
Building 535, Suite 412
Frederick, MD 21702-1201

Tel: 301-846-1714
Fax: 301-846-7119
Email: whitbyd@mail.nih.gov

Biography

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.

Research Description

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.

Recent Publications

  1. Labo N, Miley W, Marshall V, Gillette W, Esposito D, et al. (2014) Heterogeneity and breadth of host antibody response to KSHV infection demonstrated by systematic analysis of the KSHV proteome. PLoS Pathog 10: e1004046.
  2. Stolka K, Ndom P, Hemingway-Foday J, Iriondo-Perez J, Miley W, et al. (2014) Risk factors for Kaposi's sarcoma among HIV-positive individuals in a case control study in Cameroon. Cancer Epidemiol 38: 137-143.
  3. Wakeham K, Webb EL, Sebina I, Nalwoga A, Muhangi L, et al. (2013) Risk factors for seropositivity to Kaposi sarcoma-associated herpesvirus among children in Uganda. J Acquir Immune Defic Syndr 63: 228-233.
  4. Venkataraman G, Uldrick TS, Aleman K, O'Mahony D, Karcher DS, et al. (2013) Bone marrow findings in HIV-positive patients with Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Am J Clin Pathol 139: 651-661.
  5. Renteria AS, Marshall VA, Sun Y, Chockalingam P, Cooper JS, et al. (2013) A Unique Case of Classic Kaposi's sarcoma restricted to the toes. J Dermatol Case Rep 7: 97-100.
  6. Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, et al. (2013) Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood 122: 4189-4198.
  7. Maskew M, MacPhail AP, Whitby D, Egger M, Fox MP (2013) Kaposi sarcoma-associated herpes virus and response to antiretroviral therapy: a prospective study of HIV-infected adults. J Acquir Immune Defic Syndr 63: 442-448.
  8. Han SJ, Marshall V, Barsov E, Quinones O, Ray A, et al. (2013) Kaposi's sarcoma-associated herpesvirus microRNA single-nucleotide polymorphisms identified in clinical samples can affect microRNA processing, level of expression, and silencing activity. J Virol 87: 12237-12248.
  9. Gogineni E, Marshall V, Miley W, Bayat A, Whitby D, et al. (2013) Quantitative determinations of anti-Kaposi sarcoma-associated herpesvirus antibody levels in men who have sex with men. Diagn Microbiol Infect Dis 76: 56-60.
  10. Uldrick TS, Wyvill KM, Kumar P, O'Mahony D, Bernstein W, et al. (2012) Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. J Clin Oncol 30: 1476-1483.
  11. Ray A, Marshall V, Uldrick T, Leighty R, Labo N, et al. (2012) Sequence analysis of Kaposi sarcoma-associated herpesvirus (KSHV) microRNAs in patients with multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome. J Infect Dis 205: 1665-1676.
  12. Bagni R, Whitby D (2012) Age of infection and risk of virally associated cancers: new clues to an old puzzle. J Infect Dis 205: 873-874.
  13. Wakeham K, Webb EL, Sebina I, Muhangi L, Miley W, et al. (2011) Parasite infection is associated with Kaposi's sarcoma associated herpesvirus (KSHV) in Ugandan women. Infect Agent Cancer 6: 15.
  14. Uldrick TS, Whitby D (2011) Update on KSHV epidemiology, Kaposi Sarcoma pathogenesis, and treatment of Kaposi Sarcoma. Cancer Lett 305: 150-162.
  15. Uldrick TS, Polizzotto MN, Aleman K, O'Mahony D, Wyvill KM, et al. (2011) High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood 117: 6977-6986.
  16. Maskew M, Macphail AP, Whitby D, Egger M, Wallis CL, et al. (2011) Prevalence and predictors of kaposi sarcoma herpes virus seropositivity: a cross-sectional analysis of HIV-infected adults initiating ART in Johannesburg, South Africa. Infect Agent Cancer 6: 22.
  17. Benavente Y, Mbisa G, Labo N, Casabonne D, Becker N, et al. (2011) Antibodies against lytic and latent Kaposi's sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study. Br J Cancer 105: 1768-1771.
  18. Pfeiffer RM, Wheeler WA, Mbisa G, Whitby D, Goedert JJ, et al. (2010) Geographic heterogeneity of prevalence of the human herpesvirus 8 in sub-Saharan Africa: clues about etiology. Ann Epidemiol 20: 958-963.
  19. Marshall V, Martro E, Labo N, Ray A, Wang D, et al. (2010) Kaposi sarcoma (KS)-associated herpesvirus microRNA sequence analysis and KS risk in a European AIDS-KS case control study. J Infect Dis 202: 1126-1135.

Staffing

  • M. Nazzarena Labo, M.D., Scientist I
  • Brian Morrison, Ph.D., Postdoctoral Fellow
  • Vickie A. Marshall, M.S., Research Associate III
  • Wendell J. Miley, M.S., Research Associate III
  • Romin Roshan, Research Associate II