Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma (KS) tumors, pleural effusion lymphomas, and multicentric Castleman's diseases. While there is a reduction in the incidence of KS among patients receiving HAART, an increasing concern is the development and spread of drug resistant HIV-1 strains, which in turn leads to reoccurrence of KSHV-associated malignancy. Despite being this pressing human health problem, however, very little has been done thus far to study host's immune responses and potential vaccine development against KSHV infection and its associated diseases. This is primarily because of the lack of proper genetic system and animal model that support in vivo studies on KSHV replication, persistence, and pathogenesis. We have recently established a new "infectious" bacterial artificial clone of KSHV genome (BAC16) that significantly improved the efficiency of the genetic manipulation and virus production system. Besides this, we have also established the first successful zoonotic or cross-species transmission of KSHV into non-human primates, common marmosets (Callithrix jacchus). Our specific preliminary results are: (1) the KSHV BAC16 is stable and produce infectious virus (~106-7 titers);(2) common marmosets intravenously or orally inoculated with recombinant KSHV rapidly sero-converted and maintained a high anti-KSHV antibody response over a long period of time;and (3) remarkably, orally infected marmoset developed KS-like skin lesions with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These genetic and animal models significantly recapitulate the important aspects of KSHV infection in humans, thus providing a unique opportunity in developing potential vaccine strategies against KSHV infection. Thus, recombinant viruses will be constructed to determine their roles in viral infection in cultures, mice, and primates, and ultimately establish the foundations for the rationale design of vaccine candidates. Thus, the goal of this study is two-fold: firstly, to develop genetically modified KSHV strains to be used as vaccine candidates and secondly, to further build up the animal models of KSHV infection for vaccine development. This proposal is highly innovative and a successful outcome should prove to be a major discovery that significantly impacts the understanding of KSHV infection to ultimately reveal novel protective and/or therapeutic vaccine strategies.

Public Health Relevance

Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma tumors, primary effusion lymphoma, and Multicentric Castleman's disease. Despite being a pressing human health problem, there has been little or no activity so far to develop protective and/or therapeutic vaccines against KSHV infection and its associated diseases. This proposal is highly innovative and a successful outcome should prove to be a major discovery that significantly impacts the understanding of the controls of KSHV infection to ultimately reveal novel protective and/or therapeutic vaccine strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI105909-01
Application #
8510277
Study Section
Special Emphasis Panel (ZAI1-JKB-M (J5))
Program Officer
Beisel, Christopher E
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$205,000
Indirect Cost
$80,000
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089