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293 Protective Immunity in Rhesus Monkeys Immunized with Replication-Defective HIV-1 Vaccine
F. Tung*1, K. Cole2, L. Tung1, H. McClure3, and R. Montelaro2
1GeneCure LLC, Atlanta GA, USA; 2Univ. of Pittsburgh, PA, USA; and 3Emory Univ., Atlanta GA, USA
Background: Live-attenuated simian immunodeficiency virus (SIV) elicited protective immunity in rhesus monkeys. This animal model provides evidences that protective immunity can be elicited by vaccination. However, this vaccine approach was hindered by safety concerns that the live-attenuated HIV-1 may cause disease in humans.
Methods: To ensure the safety and maintain the immunogenicity of a live-attenuated vaccine, we have developed a replication-defective HIV-1 pseudotyped with vesicular stomatitis virus G protein (VSV-G) as a vaccine candidate. The polymerase gene of HIV-1 was truncated in the replication-defective HIV-1. In the second replication defection HIV-1construct, an interferon-gamma gene was coexpressed with HIV-1 proteins. The viruses were produced by cotransfecting with a construct encoding functional pol gene. The pseudotyped HIV-1 can infect many cell types including human and simian cells and only undergoes 1 cycle of replication. Four rhesus monkeys were immunized with replication-defective HIV-1 through multi-routes (oral, subcutaneous, and intramuscular).
Results: Strong immune responses (humoral and cell mediated) can be detected in the immunized animals. After challenging with SHIVku-2, all immunized animals and naïve control have transient viremia by RT-PCR. However, virus load becomes undetectable in the vaccinated animals 2 months after challenge as compared to persistent infection in control animals for over 1 year. The level of CD4 cells also maintains at normal level in the vaccinated animals as compared with a 40% drop in control animals at 44 weeks post challenge.
Conclusions: The results indicate that replication-defective HIV-1 is highly immunogenic and can elicit protective immunity. Therefore, replication defective HIV-1 may provides a safe vaccine candidate for human clinical trials.
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