HIV-1 vaccines are in various phases of clinical trials and numerous others are in the developmental pipeline. Most of these vaccines utilize plasmid DNA constructs to prime and/or boost with the goal of driving Th1-type cytotoxic CD8+ T cells recognizing multiple HIV-1 epitopes, plus/minus induction of neutralizing antibodies. Vaccines are especially needed for developing country populations where morbidity and mortality due to HIV/AIDS is most severe. The ability to drive HIV/AIDS vaccine specific Th1-type cytotoxic CD8+ T cell responses may be severely compromised because the majority of individuals in developing countries are infected with one or more helminth parasites which systemically bias the immune system towards Th2-type. This innovations proposal focuses on analyzing the ability of an HIV-1 candidate vaccine containing a known murine CTL epitope to drive Th1-type CD8+ T cell and/or antibody responses in mice which have been strongly Th2-biased via infection with the human helminth parasite Schistosoma mansoni. Because normal immune bias can be restored by eradication of helminth parasites, we propose to determine if our candidate HIV-1 vaccine will drive Th1-type cytotoxic CD8+ T cell responses in drug-cured mice. Lastly, we ask if Th1-type cytotoxic CD8+ T cell responses generated in na?ve mice following vaccination with candidate HIV-1 vaccines can be maintained in the face of chronic Th2-biased helminth infection. We hypothesize that mice chronically infected with S. mansoni will not develop the desired Th1-type, cytotoxic CD8+ T cell responses that non-infected, vaccinated mice will.
In Aim 1 we will determine the ability of mice infected with S. mansoni to respond to a candidate HIV-1 vaccine. The second Specific Aim will test if eradication of helminth infection restores vaccine responsiveness and our hypothesis is that eradication of S. mansoni infection will enable vaccine-specific Th1-type and cytotoxic CD8+ T cell responses to candidate HIV-1 vaccines.
Our third aim will examine the influence of subsequent schistosome infection on an established Th1-type vaccine response.
| Da'Dara, Akram A; Lautsch, Norman; Dudek, Timothy et al. (2006) Helminth infection suppresses T-cell immune response to HIV-DNA-based vaccine in mice. Vaccine 24:5211-9 |
