New approaches are needed to develop an effective vaccine for the prevention of HIV infection. Among the major challenges faced in designing an effective vaccine is the genetic variability of the virus and its ability to rapidly escape immune responses once it has disseminated within the infected host. HIV is most frequently acquired via mucosal exposure through sexual contact. Studies in macaques and humans have shown that SIV or HIV initially replicates locally in mucosal tissues prior to disseminating to lymphoid tissues throughout the body through the bloodstream. A vaccine that acts during early events following exposure at the local mucosal site may be more effective in limiting or preventing virus replication and subsequent dissemination. This application will take an approach to eliciting local mucosal immune responses through vaccination with parainfluenza virus type 5 (PIV5) vectors expressing SIV Gag and HIV Env and through mucosal application of Gag-Env virus-like particles (VLPs) engineered to reach the rectal mucosa-associated lymphoid tissue. PIV5 has not previously been evaluated as an HIV vaccine candidate, and is attractive due to its mucosal application and proven ability to protect at mucosal sites for other pathogens. Experiments in this proposal will define the ideal route to elicit potent intrarectal immune responses in mice and macaques. A low-dose intrarectal challenge experiment will be performed in macaques following mucosal immunization with PIV5 and rectal or intramuscular boosting with VLPs. These experiments will determine if vectors designed to stimulate potent local response in the rectal mucosa are protective from SHIV infection, and will seek to define correlates of mucosal immune protection.
New approaches are needed to develop an HIV vaccine that prevents infection. This proposal seeks to use novel vectors to generate immune responses in the rectum that can protect from the earliest events of HIV infection. This proposal will determine if local application of a new live vector HIV vaccine based on the virus PIV5 followed by administration of HIV virus-like particles in the rectum can protect monkeys from infection with an SIV/HIV chimeric (SHIV) virus.
| Iyer, Smita S; Gangadhara, Sailaja; Victor, Blandine et al. (2016) Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques. J Virol 90:8842-54 |
| Spearman, Paul (2016) HIV-1 Gag as an Antiviral Target: Development of Assembly and Maturation Inhibitors. Curr Top Med Chem 16:1154-66 |
| Williams, Katherine L; Cortez, Valerie; Dingens, Adam S et al. (2015) HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and Are Commonly Detected in Plasma From HIV-infected humans. EBioMedicine 2:1464-77 |
