Date of Award
Doctor of Philosophy (PhD)
Cell Biology, Neurobiology and Anatomy
Host cell proteins, termed restriction factors, which inhibit viral replication at various stages of the viral life cycle, determine the species-specific tropism of numerous retroviruses. Many members of the TRIM family of proteins act as viral restriction factors. One well-characterized example is the ability of TRIM5á from rhesus macaques (rhTRIM5á) to inhibit human immunodeficiency virus type-1 (HIV-1) soon after viral entry but prior to reverse transcription (RT). It is well established that the restriction requires an interaction between the viral capsid lattice and the B30.2/SPRY domain of TRIM5á. Following the binding of the viral core, TRIM5á mediates an event or series of events that result in the abortive disassembly of the viral core in a manner that prevents the accumulation of reverse transcription (RT) products. When the proteasome was inhibited using pharmacological drugs, TRIM5á-mediated inhibition of RT products and abortive disassembly of the viral core were relieved without affecting the ability of TRIM5á to inhibit retroviral infection. Even though parts of the mechanism of TRIM5á-mediated restriction of HIV-1 were identified, the specific roles of individual molecules have yet to be examined. In AIM 1 I identify a direct interaction between TRIM5á and the proteasome complex. Furthermore, this interaction occurs during restriction of HIV-1. Additionally, in AIM 2 I demonstrate that SUMO-1 and SUMO interacting motifs (SIMs) are important for TRIM5á restriction of HIV-1 and TRIM5á stability.
As mentioned before, the viral capsid is the determinant of TRIM5-mediated restriction. The capsid houses the viral RNA and other necessary proteins for a productive infection. However, the precise process of HIV-1 uncoating is still unknown. Studies suggest that the process of uncoating is modulated by viral and cellular factors. Previously, HIV-1 was shown to traffic on microtubules, in a dynein and kinesin dependent mechanism. However, key host proteins that mediate uncoating of the core are unknown. In AIM 3 I show that HIV-1 utilizes microtubules, and in particular dynein to facilitate uncoating of the core.
This dissertation further establishes that HIV-1 core interacts with various proteins in the host during early events of the viral life cycle.
Lukic, Zana, "Host Proteins Interact with the Hiv-1 Core to Facilitate and Restrict" (2014). Dissertations. 1283.
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Copyright © 2014 Zana Lukic