AIDS and Cancer Virus Program

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 in three major areas: Kaposi’s sarcoma-associated herpesvirus (KSHV) and related malignancies, the role of viruses in the etiology of lymphoma and the lastly the search for new cancer causing viruses. 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 South Africa and Uganda 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 and also occurs in HIV negative subjects (Classic KS) with a distinct geographic distribution, being rare in Asia, the US and most of Europe and relatively common in areas of the Mediterranean and sub-Saharan Africa. Our studies on KSHV include large epidemiological studies, molecular virology and translational research with a focus on the role of reactivation in transmission and pathogenesis. Related research on viral evolution and recombination includes variations in the recently described virally encoded microRNAs with functional potential

KSHV and EBV are lymphotropic viruses that are important causes of lymphomas especially in AIDS patients. We have developed whole genome viral expression arrays for KSHV and EBV and used these to study changes in viral gene expression during reactivation in lymphoma cell lines as well as in translational studies. We have developed in vitro models for studying the role of KSHV and EBV in lymphomagenesis and KSHV in KS transmission. In addition I am studying the etiology of lymphoma in the context of several large international case control studies.

It has been estimated that 15% of human cancer is attributable to known infectious causes. There remain other malignancies where epidemiological evidence suggests an infectious etiology but the agent remains unknown. The potential benefits to public health and cancer research of discovering additional oncogenic viruses are substantial, but the difficulties of conducting research to achieve this goal are equally substantial. My lab has developed a number of techniques to search for oncogenic viruses including consensus PCR assays for herpesviruses and retroviruses and more recently custom microarrays and molecular tools based on high throughput sequencing.

Recent Publications

1. Uldrick TS, Whitby D: Update on KSHV-epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett 305(2):150-62, 2011. Epub 2011 Mar 4. PMID: 21377267
2. Zavitsanou A, Malliori M, Sypsa V, Petrodaskalaki M, Psichogiou M, Rokka C, Giannopoulos A, Kalapothaki V, Whitby D, Hatzakis A: Seroepidemiology of human herpesvirus 8 (HHV-8) infection in injecting drug users. Epidemiol Infect 138(3):403-408, 2010. Epub 2009 Aug 24. PMID: 1968211.
3. Mbisa GL, Miley W, Gamache CJ, Gillette WK, Esposito D, Hopkins R, Busch MP, Schreiber GB, Little RF, Yarchoan R, Ortiz-Conde BA, Labò N, Whitby D: Detection of antibodies to Kaposi's sarcoma-associated herpesvirus: a new approach using K8.1 ELISA and a newly developed recombinant LANA ELISA. J Immunol Methods 356(1-2):39-46, 2010. Epub 2010 Mar 4. PMID: 20211626.
4. Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, Marshall V, Steinberg SM, Pittaluga S, Maric I, Whitby D, Tosato G, Little RF, Yarchoan R: An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without multicentric Castleman disease. Clinical Infect Dis 51(3):350-358, 2010. PMID: 20583924.
5. Roth MJ, Katki HA, Wei WQ, Qiao YL, Bagni R, Wang GQ, Whitby D, Dong ZW, Gail MH, Limburg PJ, Giffen CA, Taylor PR, Dawsey SM: Serum cytokine analysis in a positive chemoprevention trial: selenium, interleukin-2, and an association with squamous preneoplastic disease. Cancer Prev Res 3(7):810-817, 2010. Epub 2010 Jun 29. PMID: 20587703.
6. Marshall V, Martro E, Labo M, Ray A, Wang D, Mbisa G, Bagni RK, Volfosky N, Casabona J, Whitby D, Euro-Shaks Study Group: Kaposi sarcoma (KS)-associated herpesvirus microRNA sequence analysis and KS risk in a European AIDS-KS case control study. J Infect Dis 202(7):1126-1135, 2010. PMID: 20715927
7. Malope-Kgokong BI, Macphail P, Mbisa G, Ratshikhopha E, Maskew M, Stein L, Sitas F, Whitby D: Kaposi's sarcoma associated-herpes virus (KSHV) seroprevalence in pregnant women in South Africa. Infect Agent Cancer 5:14, 2010. PMID: 20807396
8. Zanetti E, Barozzi P, Brown EE, Bosco R, Vallerini D, Riva G, Quadrelli C, Potenza L, Forghieri F, Montagnani G, D'Amico R, Del Giovane C, Duraes C, Whitby D, Machado JC, Schulz TF, Torelli G, Luppi M: Common vascular endothelial growth factor variants and risk for posttransplant Kaposi sarcoma. Transplantation 90(3):337-338, 2010. PMID: 20683431
9. Pfeiffer RM, Wheeler WA, Mbisa G, Whitby D, Goedert JJ, de Thé G, Mbulaiteye SM: Geographic heterogeneity of prevalence of the human herpesvirus 8 in sub-Saharan Africa: clues about etiology. Ann Epidemiol 20(12):958-63, 2010. PMID: 21074111
10. Mbisa GL, Miley W, Gamache CJ, Gillette WK, Esposito D, Hopkins R, Busch MP, Schreiber GB, Little RF, Yarchoan R, Ortiz-Conde BA, Labò N, Whitby D: Detection of antibodies to Kaposi's sarcoma-associated herpesvirus: a new approach using K8.1 ELISA and a newly developed recombinant LANA ELISA. J Immunol Methods 356(1-2):39-46, 2010. Epub 2010 Mar 4. PMID: 20211626.
11. Burbelo PD, Leahy HP, Groot S, Bishop LR, Miley W, Whitby D, Kovacs JA: A four antigen mixture containing V-cyclin for serological screening of HHV-8 infection. Clin Vaccine Immunol 16:621-627, 2009.
12. Butler LM, Dorsey G, Hladik W, Rosenthal PJ, Brander C, Neilands TB, Mbisa G, Whitby D, Kiepiela P, Mosam A, Mzolo S, Dollard SC, Martin JN: Kaposi sarcoma-associated herpesvirus (KSHV) seroprevalence in population-based samples of African children: Evidence for at least 2 patterns of KSHV transmission. J Infect Dis 200:430-438, 2009.
13. Bagni R, Whitby D: Kaposi's sarcoma-associated herpesvirus transmission and primary infection. Curr Opin HIV AIDS 4:22-26, 2009.
14. deSanjose S, Mbisa G, Perez-Alvarez S, Benavente Y, Sukvirach S, Hieu NT, Shin HR, Anh PT, Thomas J, Lazcano E, Matos E, Herrero R, Munoz N, Molano M, Franceschi S, Whitby D: Geographic variation in the prevalence of Kaposi sarcoma-associated herpesvirus and risk factors for transmission. J Infect Dis 199:1449-1456, 2009.
15. Whitby D: Searching for targets of viral microRNAs. Nat Genet 41:7-8, 2009.
16. Barozzi P, Potenza L, Riva G, Vallerini D, Quadrelli C, Bosco R, Morselli M, Forghieri F, Volzone F, Rossi G, Ferri C, Bonini C, Ciceri F, Bordignon C, Whitby D, Schulz TF, Torelli G, Luppi M: Changes in T-cell responses against human herpesvirus-8 correlate with the disease course of iatrogenic Kapsoi’s sarcoma in a patient with undifferentiated arthritis. Semin Arthritis Rheum 39(3):170-175, 2009. Epub 2008 Jul 17. PMID: 18639317
17. Nunez-Troconis J, Delgado M, Gonzalez J, Mindiola R, Velasquez J, Conde B, Whitby D, Munroe DJ: Prevalence and risk factors of human papillomavirus infection in asymptomatic women in a Venezuelan urban area. Invest Clin 50(2):203-212, 2009. PMID: 19662815.
18. Pelser C, Vitale F, Whitby D, Graubard BI, Messina A, Gafa L, Brown EE, Anderson LA, Romano N, Lauria C, Goedert JJ: Socio-economic and other correlates of Kaposi sarcoma-associated herpesvirus seroprevalence among older adults in Sicily. J Med Virol 81(11):1938-1944, 2009. PMID: 19777527.
19. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V, Whitby D, WHO International Agency for Research on Cancer Monograph Working Group Members: A review of human carcinogens--Part B: Biological agents. Lancet Oncol 10(4):321-322, 2009. PMID: 19350698.
20. Núñez-Troconis J, Delgado M, González J, Velásquez J, Mindiola R, Whitby D, Conde B, Munroe DJ: Human papillomavirus false positive cytological diagnosis in low grade squamous intraepithelial lesion. Invest Clin 50(4):447-454, 2009. PMID: 20306718.
21. Nsubuga MM, Biggar RJ, Combs S, Marshall V, Mbisa G, Kambugu F, Mehta M, Biryahwaho B, Rabkin CS, Whitby D, Mbulaiteye SM: Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions. Cancer Lett 263:182-188, 2008.
22. Anderson LA, Li Y, Graubard BI, Whitby D, Mbisa G, Tan S, Goedert JJ, Engels EA: Human herpesvirus 8 seroprevalence among children and adolescents in the United States. Pediatr Infect Dis J 27:661-664, 2008.
23. Barozzi P, Bonini C, Potenza L, Masetti M, Cappelli G, Gruarin P, Whitby D, Gerunda GE, Mondino A, Riva G, Vallerini D, Quadrelli C, Bosco R, Ciceri F, Bordignon C, Schulz TF, Torelli G, Luppi M: Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma. Transplantation 86:738-744, 2008.
24. Goedert JJ, Scoppio BM, Pfeiffer R, Neve L, Federici AB, Long LR, Dolan BM, Brambati M, Bellinvia M, Lauria C, Preiss L, Boneschi V, Whitby D, Brambilla L: Treatment of classic Kaposi sarcoma with a nicotine dermal patch: A phase II clinical trial. J Eur Acad Dermatol Venereol 22:1101-1109, 2008.
25. Waldman M, Marshall V, Whitby D, Kopp JB: Viruses and kidney disease: beyond HIV. Semin Nephrol 28(6):595-607, 2008.
26. Anderson LA, Lauria C, Romano N, Brown EE, Whitby D, Graubard BI, Li Y, Messina A, Gafà L, Vitale F, Goedert JJ. Risk factors for classical Kaposi sarcoma in a population-based case-control study in Sicily. Cancer Epidemiol Biomarkers Prev 17(12):3435-43, 2008.
27. Huang WY, Hayes R, Pfeiffer R, Viscidi RP, Lee FK, Wang YF, Reding D, Whitby D, Papp JR, Rabkin CS. Sexually transmissible infections and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 17(9):2374-2381, 2008.
28. Mbulaiteye SM, Pfeiffer RM, Dolan B, Tsang VC, Noh J, Mikhail NN, Abdel-Hamid M, Hashem M, Whitby D, Thomas Strickland G, Goedert JJ: Seroprevalence and risk factors for human herpesvirus 8 infection, rural Egypt. Emerg Infect Dis 14(4):586-591, 2008. PMID: 18394276.
29. Malope BI, MacPhail P, Mbisa G, MacPhail C, Stein L, Ratshikhopha EM, Ndhlovu L, Sitas F, Whitby D: No evidence of sexual transmission of Kaposi’s sarcoma herpes virus in a heterosexual South African population. AIDS 22:519-526, 2008.

Staffing

• M. Nazzarena Labo, 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