The overall goal of this HIV Vaccine Research and Development grant competing renewal application is to study the mechanisms and feasibility of using HSV recombinants expressing AIDS viral proteins to induce protective immune responses against SIV or HIV. This research program will focus on the design, characterization, and optimization of HSV recombinant vectors expressing SIV and HIV proteins. A novel feature of this program is the recent observation that HSV vector immunization induced cellular memory responses and reduction of viral load following intravenous challenge by pathogenic SIV in rhesus macaques. Thus, the Program will focus on the novel properties of the HSV vectors and the types of memory immune responses that they induce in nonhuman primates. The individual projects and cores in this current application are summarized as follows: David Knipe. Development of HSV Vectors as AIDS Vaccines. This project will conduct studies to test several hypotheses regarding the basic properties of herpes simplex virus vectors that have multiple immediate early genes mutated and to optimize the expression and immunogenicity of HIV and SIV proteins. Amitinder Kaur and Ron Desrosiers Immune Responses and Protection in Macaques Immunized with HSV Vaccine Vectors. This project will examine the nature of immunologic memory induced by different recombinant HSV immunization protocols and determine how it relates to protection against SIV infection of rhesus macaques. Administrative Core. The Administrative Core will 1) provide Program leadership for integration of the projects and cores and in the decisions about the use of recombinant HSV vectors in primate studies and the selection of HSV recombinants for clinical development and 2) provide administrative support for the conduct of the research proposed in this application. Immunology Core. The Immunology Core will conduct immunological assays on cells and serum from mice immunized in Project 1 and from rhesus macaques. Cellular assays will include ELISPOT, intracellular cytokine staining, and 10-color flow cytometry. Antibody assays will include ELISA and neutralization assays for SIV and HSV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046006-09
Application #
7409683
Study Section
Special Emphasis Panel (ZAI1-EC-A (M2))
Program Officer
Mehra, Vijay L
Project Start
1999-09-15
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$1,226,620
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
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
Brockman, Mark A; Knipe, David M (2008) Herpes simplex virus as a tool to define the role of complement in the immune response to peripheral infection. Vaccine 26 Suppl 8:I94-9
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
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
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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