Antiretroviral therapy (ART) is not sufficient to control human immunodeficiency virus (HIV) infection, and therapeutic approaches to stimulate virus-specific immune responses, particularly T cell responses, are urgently needed. The ideal antigen source for vaccine delivery during active infection is autologous virus, because it contains all antigens appropriate to the specific infection. Delivery of viral antigens via dendritic cells (DC) would be optimal, as DC are professional antigen-presenting cells that potently stimulate T cell responses in vivo. Dr Barratt-Boyes and colleagues have shown that DC have a unique capacity to acquire antigens from live cells for cross-presentation to T cells. DC also acquire antigens from free viral particles and from apoptotic and necrotic cells. Using the rhesus macaquehimian immunodeficiency virus (SIV) model, Dr. Barratt-Boyes and colleagues will compare these methods of acquisition of antigen by DC for the purposes of stimulating virus-specific T cell responses. Using the optimal method of providing viral antigens for cross-presentation, they will develop a DC-based tailor-made therapeutic vaccine for SIV infection using autologous viral antigens. Monkeys will be vaccinated during chronic SIV infection with a primary virus isolate and while receiving ART, to approximate clinical HIV infection and therapy. The studies aim to provide an importanl proof-of-principle for using autologous, whole virus vaccines for the treatment of established HIV infection. There are 3 specific aims: (1) To characterize and optimize cross- presentation of SIV antigens b j monkey DC in vitro; (2) To determine the capacity for DC to stimulate polyclonal T cell responses to autologous SIV in vitro; and (3) To test the capacity for antigen-loaded DC to augment immunity to autologous SIV in vivo.
| Melhem, Nada M; Gleason, Sherrianne M; Liu, Xiang Dong et al. (2008) High-level antigen expression and sustained antigen presentation in dendritic cells nucleofected with wild-type viral mRNA but not DNA. Clin Vaccine Immunol 15:1337-44 |
| Melhem, Nada M; Liu, Xiang Dong; Boczkowski, David et al. (2007) Robust CD4+ and CD8+ T cell responses to SIV using mRNA-transfected DC expressing autologous viral Ag. Eur J Immunol 37:2164-73 |
| Barratt-Boyes, Simon M; Brown, Kevin N; Melhem, Nada et al. (2006) Understanding and exploiting dendritic cells in human immunodeficiency virus infection using the nonhuman primate model. Immunol Res 36:265-74 |
| Barratt-Boyes, S M; Thomson, A W (2005) Dendritic cells: tools and targets for transplant tolerance. Am J Transplant 5:2807-13 |
