Dendritic cells (DCs) are specialized members of the innate immune system that are responsible for the initiation of primary adaptive immune responses whose purpose is to resolve infection and inflammation. During most viral infections, mature dendritic cells present critical viral antigens to naïve T-cells within secondary lymphoid organs, resulting in the generation of an antigen-specific adaptive immune response and clearance of the virus. During infection with HIV-1 however, the virus is not cleared and a chronic systemic infection develops characterized by immune dysfunction, CD4+ T-cell depletion, systemic inflammation, and opportunistic infections. A growing body of evidence indicates that HIV-1 subversion of DCs contributes to both HIV-1 pathologies and viral dissemination. A number of similar effects by accessory HIV-1 peptides on DC physiology have also been reported. In vitro studies demonstrate that HIV-1 inhibits DC maturation and function. Ex vivo studies on the other hand describe partially mature, dysfunctional DCs collecting in secondary lymphoid organs. In vitro studies examining the effects of HIV-1-Tat and HIV-1-Vpr have described opposing effects on DC maturation. Therefore we undertook experiments to comprehensively describe the effects of HIV-1 and the Tat and Vpr accessory peptides on DC maturation and function. To understand the contributions of individual viral proteins to DC dysfunction we infected DCs with a dual tropic HIV-1 and examined phenotypic and functional changes after maturation with inflammatory cytokines. Following this we examined the influence of exogenous and endogenous HIV-1-Tat and HIV-1-Vpr on MDDC maturation and function using recombinant proteins and deletion mutant lab adapted HIV-1 strains. Live dual tropic HIV-1 was found to selectively inhibit aspects of phenotypic maturation as well as antigen capture and presentation functions. MDDC MAPK responsiveness to bacterial LPS remained intact however. Exogenous accessory HIV-1 Tat and Vpr did not affect MDDC phenotype but inhibited dextran endocytosis and viral peptide presentation. HIV-1-gp120 increased iMDDC maturation while blunting cytokine induced decreases in MDDC antigen capture abilities. The deletion of HIV-1-Tat did not affect MDDC phenotype, but was found to affect antigen capture decreases by R5 tropic HIV-1BaL. Deletion of HIV-1-Vpr likewise did not affect MDDC phenotype, however it was found to be influential in HIV-1 induced decreases in MDDC antigen presentation to autologous T-cells. These accumulated results indicate that HIV-1 subverts DC maturation and function through whole virus effects and individual accessory peptide influences. Understanding the mechanisms of DC dysfunction in HIV infection may provide some insight into infection prevention strategies and therapies leading to adaptive immune system activation and viral clearance.

Herein we describe a novel APC population in mice, designated LAPCs. LAPCs are BM-derived myeloid leukocytes, distinctive from other immune cells. As APCs, LAPCs respond to various virus infections including VACV, CBV3 and influenza A virus. Notably, influenza virus-activated LAPCs capture Ag in the lungs, and migrate into the DLN and spleen with delayed kinetics compared to DCs. In the DLN, influenza virus-activated LAPCs co-localize with T cells and selectively induce Th2 effector cell polarization by cell-cell contact-mediated modulation of GATA-3 expression. In support of a role for LAPCs in anti-influenza T2 immunity, adoptive transfer experiments revealed that influenza virus-activated LAPCs selectively augmented Th2 effector T cell responses in the DLN, increased production of anti-influenza immunoglobulin (Ig) including IgE in peripheral blood and increased levels of IL-5 and eotaxin in BAL fluid in recipient influenza infected mice. LAPC recipient mice exhibited exacerbated pulmonary pathology, with delayed viral clearance and enhanced pulmonary eosinophilia. Collectively, these results highlight the importance of LAPCs as novel immuno-modulators of T2 immunity during influenza A virus infection, which is implicated in both immunoprotection and immunopathology. Subsequently, we examined the immuno-modulatory effect of type-I IFN, specifically IFN-on the immune response against pulmonary influenza virus infection. We have provided evidence that a single dose of IFN- (1×105U) augmented DC migration but inhibited LAPC migration into the DLN. mIFN- treatment skewed the immune balance toward T1 immunity, identified as enhanced T1 effector T cell responses (Th1 and CTL) but diminished T2 effector T cell responses (Th2) in influenza virus infected mice. Finally, IFN- treated mice showed accelerated viral clearance and diminished pulmonary eosinophilia in lung tissue compared to control mice. Taken together, these results suggest that anti-influenza T1 and T2 immunity may be modulated differently by DCs and LAPCs, respectively. Furthermore, these results support the therapeutic potential of type I IFNs, especially IFN-, as an alternative antiviral to control both viral replication and immunopathology induced by influenza A virus infection in humans.

Includes bibliography (leaves 217-239). / xxviii, 239 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Undertakes a detailed characterisation of the molecular phenotypes of the various antigen presenting cell populations present in the uterus, with a particular focus on the cells present at estrus, following insemination, and at the time of embryo implantation (day 4 of pregnancy). / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 2000

Typescript (photocopy) / viii, 102, xxv leaves, [6] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.) Dept. of Microbiology, University of Adelaide, 1982

Thesis (Ph. D.)--University of Adelaide, 1986. / Offprints of author's four journal articles in pocket. Includes bibliographical references (leaves 131-147).

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Hohenheim, University, Diss., 2005.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 5 uppsatser.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: pp. 124-137

Thesis (Ph.D.) Dept. of Microbiology, University of Adelaide, 1982. / Typescript (photocopy).