Animal models are invaluable tools to further the understanding of human disease transmission or pathogenesis. In the context of human immunodeficiency virus (HIV), non-human primate models are frequently used to answer questions too costly, impractical or unethical to address in human clinical science. We sought to develop the model of simian immunodeficiency virus (SIV) as an alternative to simian/human immunodeficiency virus (SHIV), specifically focusing on passive immunization, by identifying and characterizing a panel of monoclonal antibodies (mAbs) targeting the viral envelope. The most promising of these mAbs were then advanced to in vivo NHP studies to characterize delivery platforms, specifically vectored immunoprophylaxis (VIP) via adenoassociated virus (AAV). Macaques were passively immunized therapeutically and prophylactically with anti-SIV Envelope mAbs. The goal of these studies was to determine if this model of passive immunization could predict outcomes of anti-HIV broadly neutralizing antibody (bNAb) based interventions against transmission or pathogenesis. The resulting protection observed in these studies highlights the discrepancies between different NHP models (SHIV vs SIV). Knowing which model to choose for a particular clinical candidate will be crucial for conserving resources, effort and time spent conducting human studies. These studies have laid the ground work for predicting the in vivo utility of NHP models for a myriad of passive vaccine concepts, including antibody infusion, VIP, chimeric antigen receptor T cells, and bi/tri-specific antibody technologies. Additionally, the characterization of VIP here has clinical implications for optimizing delivery of antibodies. Lastly, the characterization of these antibodies in vitro has revealed virology behaviors not yet observed in HIV-1. Together, this work expands the SIV model to meet the needs of the rapidly advancing field of antibody research which is poised to translate many concepts to the clinic.
|Advisor:||Rogederer, Mario, Nixon, Douglas|
|Commitee:||Alter, Galit, Leitenberg, David, Lynch, Rebecca, Robert-Guroff, Marjorie|
|School:||The George Washington University|
|Department:||Microbiology & Immunology|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 79/05(E), Dissertation Abstracts International|
|Keywords:||AAV, HIV, Passive immunization, SIV, VIP, bNAb|
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