<scp>HIV</scp>
            ‐1 capsids mimic a microtubule regulator to coordinate early stages of infection

Silva, Eveline Santos da; Shanmugapriya, Shanmugapriya; Malikov, Viacheslav; Gu, Feng; Delaney, Michael Keegan; Naghavi, Mojgan H.

doi:10.15252/embj.2020104870

Cited by 26 publications

(29 citation statements)

References 76 publications

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“…Supporting these findings, reconstitution of endogenous reverse transcription in a cell-free system followed by cryo-electron tomographic imaging has recently suggested that capsid uncoating does not occur in an all-or-none fashion but rather as a “local lattice rupture” where the initial stages involve the loss of relatively small surface patches, through which loops of the growing viral double-stranded cDNA could extrude [ 51 ]. Although these recent in vitro studies do not address the hotly debated question of when and where reverse transcription and uncoating occur in infected cells [ 52 – 55 ], they are in line with the thinking of several groups that suggest that reverse transcription and uncoating are complex processes that begin in the cytoplasm, termed “partial uncoating”, and complete inside the nucleus [ 32 , 42 , 46 , 47 , 56 – 75 ]. Indeed, partial loss of CA protein during cytoplasmic transport of HIV-1 cores to the nucleus has been visualized by the Hope lab for particles that go on to successfully deliver and express reporter genes [ 47 ].…”

Section: The Contentious Topic Of Cytoplasmic Versus Nuclear Uncoatingmentioning

confidence: 95%

“…Recent work has shed light on how HIV-1 particles are capable of engaging several different classes of +TIPs to regulate MT dynamics together with trafficking and uncoating of viral cores, which occurs at least in part through mimicry of EB1. Beyond its direct role in regulating MT dynamics that control infection, EB1 was also found to indirectly contribute to early HIV-1 infection by delivering +TIPs such as cytoplasmic linker protein-170 (CLIP170) to the cell periphery [ 75 ] (Table 1 ). CLIP170 was shown to function differently to EB1 or other previously identified +TIPs discussed above, in that it regulates infection without significantly affecting the formation of stable MTs.…”

Section: Hiv-1 Capsid Mimicry Of Eb1mentioning

confidence: 99%

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

Naghavi

2021

Retrovirology

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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.

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Section: The Contentious Topic Of Cytoplasmic Versus Nuclear Uncoatingmentioning

confidence: 95%

Section: Hiv-1 Capsid Mimicry Of Eb1mentioning

confidence: 99%

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

Naghavi

2021

Retrovirology

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“…A number of cellular factors that participate in microtubule-dependent transport mechanisms have been shown to interact with HIV-1 CA (see [ 59 ] and [ 60 ] for recent reviews), including microtubule-associated proteins 1 (MAP1) [ 61 ], fasciculation and elongation factor zeta 1 (FEZ1) [ 62 , 63 ], diaphanous 2 (Dia2) [ 64 ], Bicaudal D2 (BICD2) [ 65 , 66 ], cytoplasmic linker-associated protein 2 (CLASP2) [ 67 ], and cytoplasmic linker protein 170 (CLIP170) [ 68 ]. Although these studies established contributions from these binding factors to HIV-1 retrograde movement within cells, it is unclear if infection would require the viral core to bind to all of these proteins simultaneously.…”

Section: The Trip To the Nucleusmentioning

confidence: 99%

HIV Capsid and Integration Targeting

Engelman

2021

Viruses

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Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear environment where the chromosomes reside. Retroviral integration is non-random, with different types of virus-host interactions impacting where in the host chromatin integration takes place. Lentiviruses such as HIV efficiently infect interphase cells because their RTCs have evolved to usurp cellular nuclear import transport mechanisms, and research over the past decade has revealed specific interactions between the HIV capsid protein and nucleoporin (Nup) proteins such as Nup358 and Nup153. The interaction of HIV capsid with cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular cleavage and polyadenylation complex, helps to dictate nuclear import as well as post-nuclear RTC invasion. In the absence of the capsid-CPSF6 interaction, RTCs are precluded from reaching nuclear speckles and gene-rich regions of chromatin known as speckle-associated domains, and instead mis-target lamina-associated domains out at the nuclear periphery. Highlighting this area of research, small molecules that inhibit capsid-host interactions important for integration site targeting are highly potent antiviral compounds.

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“…In addition to EB1, diaphanous-related formins (DRFs) have been shown to facilitate microtubule stabilization and assist in the intracellular trafficking and timed disassembly of capsid by interacting directly with the capsid core to coordinate these processes [ 84 ]. Such findings suggest a mechanism for HIV-1 to highjack host cell machinery to achieve movement in the cell [ 85 ].…”

Section: Function Of the Hiv-1 Capsidmentioning

confidence: 99%

Structure, Function, and Interactions of the HIV-1 Capsid Protein

Rossi

Meuser

Cunanan

et al. 2021

Life

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The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

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HIV ‐1 capsids mimic a microtubule regulator to coordinate early stages of infection

Cited by 26 publications

References 76 publications

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

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

HIV Capsid and Integration Targeting

Structure, Function, and Interactions of the HIV-1 Capsid Protein

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