Vesicular stomatitis virus (VSV) has been developed as a live mucosal vaccine vector and is highly effective in an influenza model system. The goal of this competitive renewal is to continue development of VSV/HIV hybrid viruses as HIV vaccines using a mouse model for initial screening of promising approaches. New strategies designed to enhance both neutralizing antibody and cell-mediated immune responses to HIV-1 proteins are being developed. Initial studies have established that complete HIV envelope protein (HIV Env) can be expressed in VSV/HIV hybrids and that incorporation of HIV Env into the VSV envelope enhances the antibody response to Env. Both antibody and strong cytotoxic T lymphocyte (CTL) responses to HIV Env have been seen in mice and in rhesus macaques infected with the vectors.
The first aim i s to test new strategies for enhancing neutralizing antibody responses to HIV Env. One strategy is based on results of others describing SIV Env mutants lacking glycosylation sites which generated high neutralizing antibody titers to the parental virus. A set of HIV env mutants lacking increasing numbers of N-linked glycans has been generated in Dr. Rose's laboratory. These will be expressed in VSV recombinants and tested in mice for induction of HIV neutralizing antibody. Additional studies will determine the effectiveness of VSV vectors encoding both Env and Gag proteins of HIV, and producing large amounts of HIV virus-like particles containing Env and Gag proteins. Boosting of the immune responses using VSV vectors is limited because antibodies to the single vector glycoprotein (G) are developed after the first immunization. A new vector system using a different G protein in the vector has been devised and will be tested in mice.
The second aim i s to quantitate the cellular immune responses to HIV Env and Gag proteins expressed in VSV vectors, and to investigate approaches to enhancing these responses.
The third aim i s to continue development of live VSV/HIV surrogate viruses that have a total replacement of the VSV envelope protein by HIV Env-G hybrid proteins. These viruses might be directly applicable as vaccines or could be used in boosting immune responses to HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040357-06
Application #
6373559
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Warren, Jon T
Project Start
1996-07-15
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
6
Fiscal Year
2001
Total Cost
$241,265
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Schell, John B; Bahl, Kapil; Folta-Stogniew, Ewa et al. (2015) Antigenic requirement for Gag in a vaccine that protects against high-dose mucosal challenge with simian immunodeficiency virus. Virology 476:405-12
Schell, John B; Bahl, Kapil; Rose, Nina F et al. (2012) Viral vectored granulocyte-macrophage colony stimulating factor inhibits vaccine protection in an SIV challenge model: protection correlates with neutralizing antibody. Vaccine 30:4233-9
Schell, John B; Rose, Nina F; Bahl, Kapil et al. (2011) Significant protection against high-dose simian immunodeficiency virus challenge conferred by a new prime-boost vaccine regimen. J Virol 85:5764-72
Schlehuber, Lisa D; Rose, John K (2004) Prediction and identification of a permissive epitope insertion site in the vesicular stomatitis virus glycoprotein. J Virol 78:5079-87
Ramsburg, Elizabeth; Rose, Nina F; Marx, Preston A et al. (2004) Highly effective control of an AIDS virus challenge in macaques by using vesicular stomatitis virus and modified vaccinia virus Ankara vaccine vectors in a single-boost protocol. J Virol 78:3930-40
Publicover, Jean; Ramsburg, Elizabeth; Rose, John K (2004) Characterization of nonpathogenic, live, viral vaccine vectors inducing potent cellular immune responses. J Virol 78:9317-24
Quinones-Kochs, Miriam I; Buonocore, Linda; Rose, John K (2002) Role of N-linked glycans in a human immunodeficiency virus envelope glycoprotein: effects on protein function and the neutralizing antibody response. J Virol 76:4199-211
Haglund, Karl; Leiner, Ingrid; Kerksiek, Kristen et al. (2002) High-level primary CD8(+) T-cell response to human immunodeficiency virus type 1 gag and env generated by vaccination with recombinant vesicular stomatitis viruses. J Virol 76:2730-8
Haglund, Karl; Leiner, Ingrid; Kerksiek, Kristen et al. (2002) Robust recall and long-term memory T-cell responses induced by prime-boost regimens with heterologous live viral vectors expressing human immunodeficiency virus type 1 Gag and Env proteins. J Virol 76:7506-17
Rose, N F; Marx, P A; Luckay, A et al. (2001) An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell 106:539-49

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