The goal of the research in this project is to construct and analyze replication competent strains of rhesus monkey rhadinovirus (RRV) that express SIV antigens at high levels. RRV is a naturally-occurring gamma herpesvirus of rhesus monkeys that can be used for experimental infection of RRV-negative animals. RRV persists in a non-pathogenic fashion for the lifespan of infected monkeys and its growth properties in culture will allow ready manipulation of the viral genome. Our discovery of this virus provides an ideal system to investigate the ability of herpesvirus recombinants to provide vaccine protection against pathogenic SIV. In addition, our recent determination of the RRV genomic DNA sequence will greatly facilitate the genetic manipulations needed for the recombinant constructions. Initial research will focus on the development of procedures for construction of deletion mutant and recombinant RRV. RRV with deletions in targeted genes will be analyzed for growth properties in permissive cells and for persistence in B cells in culture. Replication- competent strains of RRV will be constructed in which RRV genes are replaced by SIV env or gag-pol expressing cassettes. We will compare constitutive SV40 promoter versus endogenous herpesvirus promoter, rev-dependent versus rev-independent modes of expression, and different insertion sites in the RRV genome for level of expression of SIV antigens during permissive infection of rhesus monkey fibroblasts and during persistent infection of rhesus monkey B cells. Well-characterized, recombinant RRV strains expressing SIV antigens derived from these studies will be sued for vaccine testing in Project III.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI046006-01
Application #
6224540
Study Section
Special Emphasis Panel (ZAI1-KWR-A (M1))
Project Start
1999-09-15
Project End
2004-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Meythaler, Mareike; Wang, Zichun; Martinot, Amanda et al. (2011) Early induction of polyfunctional simian immunodeficiency virus (SIV)-specific T lymphocytes and rapid disappearance of SIV from lymph nodes of sooty mangabeys during primary infection. J Immunol 186:5151-61
Reszka, Natalia; Zhou, Changhong; Song, Byeongwoon et al. (2010) Simian TRIM5alpha proteins reduce replication of herpes simplex virus. Virology 398:243-50
Meythaler, Mareike; Martinot, Amanda; Wang, Zichun et al. (2009) Differential CD4+ T-lymphocyte apoptosis and bystander T-cell activation in rhesus macaques and sooty mangabeys during acute simian immunodeficiency virus infection. J Virol 83:572-83
Liu, Xueqiao; Broberg, Eeva; Watanabe, Daisuke et al. (2009) Genetic engineering of a modified herpes simplex virus 1 vaccine vector. Vaccine 27:2760-7
Cliffe, Anna R; Garber, David A; Knipe, David M (2009) Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol 83:8182-90
Meythaler, Mareike; Pryputniewicz, Sarah; Kaur, Amitinder (2008) Kinetics of T lymphocyte apoptosis and the cellular immune response in SIVmac239-infected rhesus macaques. J Med Primatol 37 Suppl 2:33-45
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Cliffe, Anna R; Knipe, David M (2008) Herpes simplex virus ICP0 promotes both histone removal and acetylation on viral DNA during lytic infection. J Virol 82:12030-8
Watanabe, Daisuke; Brockman, Mark A; Ndung'u, Thumbi et al. (2007) Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector. Virology 357:186-98
Kaur, Amitinder; Sanford, Hannah B; Garry, Deirdre et al. (2007) Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus. Virology 357:199-214

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