HIV-1 capsid exploitation of the host microtubule cytoskeleton during early infection

Abstract

Microtubules (MTs) form a filamentous array that provide both structural support and a coordinated system for the movement and organization of macromolecular cargos within the cell. As such, they play a critical role in regulating a wide range of cellular processes, from cell shape and motility to cell polarization and division. The array is radial with filament minus-ends anchored at perinuclear MT-organizing centers and filament plus-ends continuously growing and shrinking to explore and adapt to the intracellular environment. In response to environmental cues, a small subset of these highly dynamic MTs can become stabilized, acquire post-translational modifications and act as specialized tracks for cargo trafficking. MT dynamics and stability are regulated by a subset of highly specialized MT plus-end tracking proteins, known as +TIPs. Central to this is the end-binding (EB) family of proteins which specifically recognize and track growing MT plus-ends to both regulate MT polymerization directly and to mediate the accumulation of a diverse array of other +TIPs at MT ends. Moreover, interaction of EB1 and +TIPs with actin-MT cross-linking factors coordinate changes in actin and MT dynamics at the cell periphery, as well as during the transition of cargos from one network to the other. The inherent structural polarity of MTs is sensed by specialized motor proteins. In general, dynein directs trafficking of cargos towards the minus-end while most kinesins direct movement toward the plus-end. As a pathogenic cargo, HIV-1 uses the actin cytoskeleton for short-range transport most frequently at the cell periphery during entry before transiting to MTs for long-range transport to reach the nucleus. While the fundamental importance of MT networks to HIV-1 replication has long been known, recent work has begun to reveal the underlying mechanistic details by which HIV-1 engages MTs after entry into the cell. This includes mimicry of EB1 by capsid (CA) and adaptor-mediated engagement of dynein and kinesin motors to elegantly coordinate early steps in infection that include MT stabilization, uncoating (conical CA disassembly) and virus transport toward the nucleus. This review discusses recent advances in our understanding of how MT regulators and their associated motors are exploited by incoming HIV-1 capsid during early stages of infection.

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…Several viruses mimic host microtubular proteins, altering cognition at the cytoskeletal level. For example, HIV-1 imitates microtubular end-binding protein 1 (EB1), disrupting cognition directly ( Naghavi, 2021 ). Other viruses, including Influenza A and Zika, exploit the host microtubular network, while SARS-CoV-2 may accomplish the same via a tubulin-like MREL motif located in the NSP1 protein ( Simpson and Yamauchi, 2020 ; Sobhy, 2021 ).…”

Rotten to the core: antivirals targeting the HIV-1 capsid core

“…Reverse transcription, the process of converting the HIV-1 RNA genome into double-stranded cDNA, is catalyzed by the enzyme reverse transcriptase (RT) located within the capsid, which prevents exposure of the viral nucleic acid to host proteins [ 12 , 25 ]. For trafficking of viral particles to the NPC, CA interacts with the microtubule-associated proteins MAP1A and MAP1S, along with FEZ1, a kinesin-1 adaptor protein, and others [ 26 – 30 ]. At the NPC, CA interacts directly with nuclear pore proteins, including NUP358 and NUP153, both of which are essential for proper nuclear import [ 31 – 34 ].…”

Overlap Intensity: An ImageJ Macro for Analyzing the HIV-1 In Situ Uncoating Assay

“…However, we have included adjustable settings that allow for use outside of the uncoating assay. For example, the HIV viral core has been shown to associate with cellular proteins involved in microtubule trafficking and nuclear import [53]. The Overlap Intensity macro could be used to assess the amount of a cellular protein associated with the viral core at different time points or under different cellular conditions.…”