Mechanisms of Immune Evasion Mediated by HIV-1 VPU

Peter William Ramirez
T h e U n i v e r s i t y o f U t a h G r a d u a t e S c h o o l STATEMENT OF DISSERTATION APPROVAL The dissertation of Peter William Ramirez has been approved by the following supervisory committee members: Vicente Planelles , Chair ABSTRACT Human Immunodeficiency Virus Type 1 (HIV-1), the causative agent of AIDS, encodes four proteins (Nef, Vif, Vpr and Vpu) that have evolved specific roles in promoting efficient viral replication and dissemination. A key attribute of these viral factors is
more » ... heir ability to interfere with multiple host defense mechanisms through one of two ways: manipulation of the ubiquitin proteasome system (UPS) or altered intracellular protein trafficking. In particular, Vpu is a small integral membrane protein that is expressed late in the viral life cycle and found only within HIV-1 and some related simian immunodeficiency virus (SIV) isolates. Vpu antagonizes multiple cellular targets that are involved in innate and adaptive immunity, including the restriction factor BST-2, a family member of cellular "intrinsic" proteins that serve to restrict viral replication immediately following viral infection. In this work, we show that Vpu downregulates the chemokine receptor CCR7 on the surface of HIV-1-infected primary CD4 + T cells by sequestering the protein in a perinuclear compartment (the trans-Golgi Network: TGN). This compromises the migratory potential of T cells in a CCR7-dependent manner and may have major implications in HIV-1 pathogenesis. Additionally, we clarify the mechanisms by which Vpu relies on cullin-RING Ligases (CRLs), one of the largest classes of E3 Ubiquitin Ligases within the UPS, to downregulate host proteins from the cell surface. Through the use of a neddylation iv inhibitor, a post-translational modification necessary for CRL activity, we establish that Vpu-mediated BST-2, CCR7 and Natural T and B cell antigen (NTB-A) downregulation is CRL-independent. This provides further support that Vpu is a multifunctional accessory protein that has evolved several ways to interfere with its cellular targets.
doi:10.26053/0h-9ez3-m1g0 fatcat:ukzkzga3dbcsncwuwg63mt5kie