Full Name
Corby Fink
Job Title
Postdoctoral Fellow
Company
Robarts Research Institute, Western University
City (Work Address)
London
State/Province/County (Work Address)
ON
Speaker Bio
I obtained my PhD from the University of Western Ontario under the supervision of Dr. Gregory Dekaban. My research focused on the development of cell-based immunotherapies and in vivo cell tracking using fluorine-19 cellular MRI. My current work under the supervision of Dr. Jimmy Dikeakos looks at small molecule inhibitors of Nef in a transgenic mouse model and how they can function as adjuvants towards a cure for HIV/AIDS.
Abstract Title
The Adjuvant Role of Nef Inhibitors Towards a Cure for HIV/AIDS
Abstract Summary
The HIV-1 accessory protein Nef is central to HIV progression to AIDS. A key Nef pathogenic determinant is the promotion of immune evasion. This effect is exerted through Nef’s interactions with Src family tyrosine kinases (SFK) to initiate multi-kinase complex formation that culminates with the down-regulation of cell surface major histocompatibility complex class I (MHC-I). Hence, HIV-1-infected cells evade immune recognition: a central element interfering with HIV cure strategies. To resolve this, we identified a dipeptide derivative (H3-1) predicted through an in silico docking screen to disrupt the Nef-SFK interaction and exploit this interaction as a therapeutic target. H3-1 counteracted Nef-dependent MHC-I down-regulation by improving cell surface MHC-I expression in HIV-1-infected primary human CD4+ T cells in the absence of cytotoxicity across diverse HIV-1 subtypes. Furthermore, we evaluated the ability of H3-1 to enhance antigen presentation in a transgenic mouse model of AIDS-like disease. In vivo, H3-1 was rapidly cleared; however, H3-1 addition to ex vivo-cultured transgenic mouse-derived CD4+ splenocytes resulted in enhanced presentation of cell surface MHC-I when complexed to a model epitope. As a structure activity relationship analysis revealed that the peptidic structure of H3-1 is central to its in vivo instability, we next used organic synthesis to generate a peptidomimetic panel of next generation H3-1 analogues resistant to proteolytic degradation. The synthesis of next-generation H3-1 analogues with improved biostability represents a key step forward in evaluating the role of Nef-SFK inhibitors as adjuvants in a functional cure for HIV/AIDS.
Corby Fink