Defining interactions between assembling HIV-1 virions and host cell plasma membrane proteins
Year: 2013
Type: dissertation
Abstract: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS) and is a significant burden on human health. As a successful pathogen, HIV-1 is able to overcome several components of the innate and adaptive immune systems. This is facilitated by the activities of the four accessory proteins Vif, Vpr, Vpu, and Nef. The Vpu protein has been shown to target an antiviral protein, BST-2/tetherin, which inhibits the release of many enveloped viruses from infected cells. While much is known about the mechanism of tetherin antagonism by Vpu, the antiviral function of tetherin is poorly understood. It has been observed that tetherin is specifically recruited to sites of HIV-1 assembly, but the mechanism of this recruitment is unknown. In my thesis work I have employed conventional and super-resolution microscopy techniques to determine the mechanism of tetherin recruitment to HIV-1 assembly sites. I have determined that both membrane curvature, mediated by the HIV-1 Gag protein, as well as interactions between Gag and the ESCRT machinery are the critical determinants of tetherin recruitment to HIV-1 assembly sites. I have also demonstrated that low levels of tetherin recruitment, induced by membrane curvature, are sufficient for inhibition of HIV-1 release. Currently I am employing super-resolution microscopy to study interactions between HIV and other host proteins. Previously, we have shown that HIV interacts with and reorganizes plasma membrane microdomains in infected cells. In polarized T cells, which are a natural host of HIV-1 infection in vivo, we have shown that multimerization of Gag mediates polarization of HIV-1 particles to a rear-end protrusion termed the uropod. Several proteins co-polarize with Gag to uropods, in a manner dependent upon the matrix domain of Gag. My current work involves characterization of interactions between HIV-1 and PSGL-1, a protein which is specifically recruited to virus assembly sites in T cells. I have found that basic residues within the cytoplasmic tail of this protein are required for its recruitment to HIV-1 assembly sites. I am also employing conventional assays to examine the affects of various uropod-directed proteins, such as PSGL-1, on HIV-1 replication and dissemination.
Author: Jonathan R. Grover
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W34178795