Induction of T cell immunity to simian immunodeficiency virus (SIV)

Erwin Schrödinger Fellowship J 1947 Induction of T cell immunity to simian immunodeficiency virus (SIV) Ines FRANK 26.6.2000 The SIV-macaque model is one of the best animal models to study human immunodeficiency virus (HIV) infection and the development of immunodeficiencies in vivo. Morphologic and genetic similarities between HIV and simian immunodeficiency virus (SIV) along with the comparable pathogenesis of SIV infection make this system useful to elucidate disease pathogenesis as well as vaccine candidates and immunotherapies that are able to induce protective immunity against SIV infection or disease. Systemic infection occurs after exposure of macaques to SIV via various routes. Similar to HIV infection in humans, infection with SIV causes an AIDS-like disease with opportunistic infections and tumors. SIV and HIV are also similar in that both have tropism for CD4 positive T cells and use similar members of the chemokine receptor family as co-receptors. Furthermore, HLA-A and -B locus homologues are found in macaques, and both human and macaque NMC class I molecules appear to bind gag and env epitopes from similar regions of both HIV and SIV; conserved MHC I binding capabilities exist between macaques and humans. Studies have also revealed that dendritic cells (DCs), natures most potent antigen presenting cells (APCs), and T cells from macaques are comparable to their human counterparts in phenotype, function, and the way they interact with immunodeficiency viruses. Much like in the human system, macaque DCs can collaborate with syngeneic T cells to promote SIV replication. Virus-producing syncytia are observed in these co-cultures. Syncytia containing large amounts of HIV RNA and viral proteins have also been identified within the similar DC-T cell locales in vivo. Therefore, significant replication of pathogenic HIV/SIV can occur in this naturally occurring DC-T cell setting. However, the main function of DCs is to activate T cells in lymph nodes. Therefore, DCs are probably involved in two arms of viral pathogenesis: (i) promoting virus replication in acute and chronic states of infection, and ii) inducing virus-specific immune responses. Using DCs, we are investigating the capacity of an inactivated SIV to induce SIV-specific T cell responses in vitro and in vivo. Additionally, we are investigating how the transient vaccine-effect induced by a live, attenuated SIV defective in nef is induced.