Kaposi sarcoma (KS) is the most common HIV-associated malignancy worldwide and causes significant morbidity and mortality, particularly in sub-Saharan Africa. Human herpesvirus-8 (HHV-8) is the etiologic agent of KS, but the natural history of progression from asymptomatic HHV-8 infection to KS development is poorly understood. Viral genomic diversity plays an important role in the risk of cancer and response to treatment in some oncogenic viruses, but HHV-8 genomic heterogeneity has been described in only limited regions of the viral genome and the potential contribution of HHV-8 diversity to KS pathogenesis and treatment outcomes is unknown. The overarching goal of this project is to provide the first comprehensive description of HHV-8 genome diversity, at the individual and population level, and to evaluate the association of HHV-8 polymorphisms with disease state and therapeutic response. Using state-of-the-art molecular technologies, we propose to determine sequence diversity over the whole HHV-8 genome in specimens from well-annotated cohorts of HHV-8/HIV-1 co-infected persons with and without KS in Uganda.
In Aim 1, we will comprehensively characterize HHV-8 diversity to define common polymorphisms and phylogenetic groupings across the cohort population.
In Aim 2, we will perform single-genome sequence analysis of polymorphic HHV-8 regions in additional paired oral, plasma and tumor specimens within individuals to determine whether multiple viral variants coexist and whether there is compartmentalization of variants in different anatomic sites.
In Aim 3, we will explore associations of HHV-8 polymorphisms with KS disease state and treatment outcomes to identify polymorphisms with potential biologic significance, which may ultimately serve as predictive or treatment-selective biomarkers or targets of therapy.

Public Health Relevance

The proposed study will define HHV-8 genomic diversity and identify common polymorphisms in HHV-8/HIV-1 co-infected persons with and without KS. This effort will enable the discovery of potential predictive and treatment-selective biomarkers and novel therapeutic targets on HHV-8, and determine the impact of KS treatment on residual virus.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54CA190146-01
Application #
8926065
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M2))
Program Officer
Dominguez, Geraldina
Project Start
Project End
Budget Start
2014-09-17
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$249,362
Indirect Cost
$70,832
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109