The goal of this project is to use herpes simplex virus (HSV) as a vaccine vector to express simian immunodeficiency virus (SIV) proteins as a new approach to elicit immunity against SIV in inoculated animals. We have isolated three HSV-1 recombinants that express SIV env protein. In this application we want to exploit several recent important observations that promise approaches to make better to promise approaches to make better vectors. We propose to make HSV type 2 recombinant strains that express SIV and HIV env and gag from rev-independent mutant genes provide by Dr. George Pavlakis. Our hypothesis is that herpesviruses can be genetically modified to provide safe viral vectors for AIDS vaccines that possess some of the same biological properties as AIDS viruses. First, herpes viruses, like HIV replication-defective HSV strains seem to induce durable immune responses in mouse model systems. Second, herpes viruses activate a strong cellular immune response without the risk of killing T cells. Thus, our hope is that the herpesvirus recombinant vectors can induce a robust cellular response against AIDS virus antigens that is continually activated and eliminated any HIV or SIV infected cell soon after infection. In this application our specific aims are 1) To construct and characterize HSV-2 recombinant strains that are replication-defective and express SIV env and gag from rev-independent genes, 2) To construct and characterize HSV-2 thymidine kinase-negative recombinant strains that are replication-competent and express SIV env and gag, 3) To identify HSV- 2 genes other than TK whose inactivation leads to HSV-2 mutant strains that are attenuated, but competent for establishment of and reactivation from latent infection in mice, 4) To use the mutant strains identified in specific aim 3 and to construct HSV-2 recombinant strains that are attenuated, replication-competent and latency competent and express SIV env and gag, and 5) To isolate HSV-2 recombinant strains expressing human immunodeficiency virus (HIV) gag and/or env.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046006-03
Application #
6503395
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
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
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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