Currently, use of macaques to evaluate efficacy of HIV vaccines has shown that although numerous types of vaccines can blunt acute infections by pathogenic challenge viruses, no vaccine can predictably prevent infection and the inevitable establishment of viral latency that accompanies the infection. The burden on the vaccine therefore is to maintain protective responses to prevent rebound of the virus from latently infected cells. The increasing incidence of virus breakthroughs after years of protection suggests that it may be necessary to administer post-exposure boosts at regular intervals in order to indefinitely maintain prevention of virus rebound. With this in mind, we investigated the feasibility of using a new type of DNA vaccine that could be used prophylactically and continued after exposure to pathogenic virus. We chose SHIVku2 DNA as a lentiviral vector that expresses several HIV genes, among which are the env and gag that can be tailored to match the genes of any particular subtype of HIV. The vaccine backbone consists of SIV promoter/enhancer sequences driving expression of the high-replication-competent SHIVku2 genome from which the rt, integrase, vif, and 3 'LTR were deleted (delta4), and the rev and tat retained. Proof of concept has shown that the delta4 DNA expressing SIV gag and X4 HIV env induced protection against heterologous X4 SHIV without the benefit of viral protein boosts and that immunization could be continued following challenge. However, proof of efficacy against R5 viruses of different subtypes would require availability of pathogenic SHIVs expressing the env/gag of these viruses.
In Aim 1 of this proposal, we will develop new pathogenic SHIVs that express the env/gag of patient isolates of subtypes B and C by incorporating these genes into the genome of highly pathogenic SHIVku2. These viruses will then be used in Aim 3 as challenge to test the efficacy of new delta4 SHIV DNA vaccines expressing env and gag of HIV subtypes B and C. We will use DNAs of cytokines GM-CSF and IL-15 as adjuvants to boost the magnitude and duration of long term immunity induced by the already successful DNA vaccine, depending on results of studies in Aim 2, in which mice will be used to assess these potential adjuvanting effects. We will then extend the study parameters in Aim 4, where we will determine whether the DNA vaccine, possibly strengthened with the cytokine adjuvants, can be used to immunize chronically infected animals under the cover of antiretroviral therapy, to re-induce immunity that would have waned during therapy. Vaccine boosts will continue after drug therapy had been withdrawn. These studies will be applicable to HIV infected persons under HAART.
| Arrode-Bruses, Geraldine; Hegde, Ramakrishna; Jin, Yuhuai et al. (2012) Immunogenicity of a lentiviral-based DNA vaccine driven by the 5'LTR of the naturally attenuated caprine arthritis encephalitis virus (CAEV) in mice and macaques. Vaccine 30:2956-62 |
| Yankee, Thomas M; Sheffer, Darlene; Liu, Zhengian et al. (2009) Longitudinal study to assess the safety and efficacy of a live-attenuated SHIV vaccine in long term immunized rhesus macaques. Virology 383:103-11 |
| Arrode, Geraldine; Hegde, Ramakrishna; Jin, Yuhuai et al. (2008) Nef modulates the immunogenicity of Gag encoded in a non-infectious HIV DNA vaccine. Vaccine 26:3795-804 |
| Arrode, Geraldine; Hegde, Ramakrishna; Mani, Arunmani et al. (2007) Phenotypic and functional analysis of immune CD8+ T cell responses induced by a single injection of a HIV DNA vaccine in mice. J Immunol 178:2318-27 |
