The experiments proposed in this application will establish the experimental basis for the design of a human immunodeficiency virus type l (HIV) vaccine in which HIV antigens are expressed in vivo by Venezuelan equine encephalitis virus (VEE) replicons. A cocktail of VEE replicon particles (VRP) directing the expression of simian immunodeficiency virus (SIV) MA/CA and ENV have been used successfully to protect rhesus macaques against disease induced by a high dose intravenous (iv.) challenge with a virulent swarm (E660) of SIV. The VEE replicon system affords several advantages as a vaccine vector for safe and effective immunization against HIV. Among these are: I) The vectored antigen is expressed to very high level, up to 20% of the total cell protein. 2) In vivo, VRP target lyrnphoid tissues, and dendritic cells in particular, leading to induction of both humoral and cellular immunity. 3) Neither priming nor boosting is diminished by prior immunity to VEE. And 4) VRP are safe; in over 1,000 rodents and 40 macaques, no untoward effects of VRP vaccines have been observed regardless of dose or route of inoculation. Three interrelated projects will utilize VRP in rodent and macaque models to l) determine optimal design of immunogens to be included in a vaccine, 2) explore the mechanisms whereby VRP target dendritic cells in vivo as well as the consequences of dendritic cell targeting for induction of an immune response, and 3) characterize the immunological parameters which determine protection in SIV and SHIV models. The integrated results from these projects will provide fundamental information regarding immunization with lentivirus antigens and will form the basis for an intensive program to develop a VEE replicon vaccine candidate for HIV.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Pensiero, Michael N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Verma, Shefali S; Frase, Alex T; Verma, Anurag et al. (2016) PHENOME-WIDE INTERACTION STUDY (PheWIS) IN AIDS CLINICAL TRIALS GROUP DATA (ACTG). Pac Symp Biocomput 21:57-68
Fluet, M E; Whitmore, A C; Moshkoff, D A et al. (2008) Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine. Virology 370:22-32
Thompson, Joseph M; Nicholson, Michael G; Whitmore, Alan C et al. (2008) Nonmucosal alphavirus vaccination stimulates a mucosal inductive environment in the peripheral draining lymph node. J Immunol 181:574-85
Thompson, Joseph M; Whitmore, Alan C; Staats, Herman F et al. (2008) The contribution of type I interferon signaling to immunity induced by alphavirus replicon vaccines. Vaccine 26:4998-5003
Thompson, Joseph M; Whitmore, Alan C; Staats, Herman F et al. (2008) Alphavirus replicon particles acting as adjuvants promote CD8+ T cell responses to co-delivered antigen. Vaccine 26:4267-75
Tang, Y; Swanstrom, R (2008) Development and characterization of a new single cycle vaccine vector in the simian immunodeficiency virus model system. Virology 372:72-84
Cecil, Chad; West, Ande; Collier, Martha et al. (2007) Structure and immunogenicity of alternative forms of the simian immunodeficiency virus gag protein expressed using Venezuelan equine encephalitis virus replicon particles. Virology 362:362-73
Liao, Hua-Xin; Sutherland, Laura L; Xia, Shi-Mao et al. (2006) A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses. Virology 353:268-82
Thompson, Joseph M; Whitmore, Alan C; Konopka, Jennifer L et al. (2006) Mucosal and systemic adjuvant activity of alphavirus replicon particles. Proc Natl Acad Sci U S A 103:3722-7
Johnston, Robert E; Johnson, Philip R; Connell, Mary J et al. (2005) Vaccination of macaques with SIV immunogens delivered by Venezuelan equine encephalitis virus replicon particle vectors followed by a mucosal challenge with SIVsmE660. Vaccine 23:4969-79

Showing the most recent 10 out of 11 publications