Retroviral intasomes arising

Engelman, Alan; Cherepanov, Peter

doi:10.1016/j.sbi.2017.04.005

Cited by 47 publications

(41 citation statements)

References 47 publications

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“…A series of X-ray crystallographic and single-particle cryogenic electron microscopy (cryo-EM) structures determined over the past decade has clarified that the number of IN molecules required to build the intasome differs depending on the type of retrovirus (reviewed in Ref. 36). Seven retroviral genera are grouped into two subfamilies of Retroviridae: Spumavirinae, solely harboring the spumaviruses, and Orthoretrovirinae, which encompass the lentiviruses, such as HIV-1, as well as ␣-, ␤-, ␦-, ⑀-, and ␥-retroviruses.…”

Section: Intasome Structure and Functionmentioning

confidence: 99%

“…IN processes the viral DNA ends in the context of the initial stable synaptic complex (SSC), yielding the cleaved synaptic complex (CSC) after viral DNA hydrolysis. The target capture complex (TCC) describes the CSC bound to target or host DNA, whereas strand transfer yields the strand transfer complex (16, [35][36][37]43). The overall conformation of the PFV intasome structure changes little as the complex morphs from the SSC to the strand transfer complex and promotes IN 3Ј processing and strand transfer activities (16, 35,37,43,44).…”

Section: Intasome Structure and Functionmentioning

confidence: 99%

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Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Engelman

2019

Journal of Biological Chemistry

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Figure 3. Retroviral intasome structures. A-C, representative intasomes from the spumavirus PFV (A; protein database (PDB) accession code 3OY9), ␤-retrovirus MMTV (B; PDB code 3JCA), and lentivirus MVV (C; PDB code 5M0Q) are color-coded to highlight the CIC. Green and blue, catalytically active IN protomers; cyan, supporting IN CCDs; black, DNA strands. Whereas four PFV IN molecules suffice to form the CIC, both MMTV and MVV require six IN protomers. For MMTV, critical CTDs (magenta) are donated by flanking IN dimers, leading to an overall IN octamer. In MVV, flanking IN tetramers provide the critical CTDs, resulting in an overall IN hexadecamer. Gray coloring in B and C deemphasizes IN elements that do not compose the CIC. D-F, resected CCD and CTD domains from above green IN protomers, oriented to highlight the different CCD-CTD linker regions (dark gray). Associated magenta CTDs from separate IN protomers in E and F assume similar positions as the green CTD in D. Red sticks, DDE catalytic triad residues. JBC REVIEWS: HIV integrase mechanisms and inhibition 15140 Figure 4. INSTI structures and ALLINI chemotypes. A, diagrams of the four FDA-licensed INSTIs as well as investigational second-generation compound 6p (113, 119). B, representative ALLINI chemotypes. Asterisks mark common positions of t-butoxyacid moieties. JBC REVIEWS: HIV integrase mechanisms and inhibition 15142

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Section: Intasome Structure and Functionmentioning

confidence: 99%

Section: Intasome Structure and Functionmentioning

confidence: 99%

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Engelman

2019

Journal of Biological Chemistry

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“…Intriguing new cryo-EM studies have identified structures for HIV IN containing more than four IN molecules. The relative contributions of these higher order structures to integration and interactions with elements of the PIC remain uncertain and are topics of active investigation [ 135 ]. The development of a new class of IN inhibitors, called allosteric integrase inhibitors (ALLINIs), will be particularly useful probes in understanding the role of higher order structures in HIV IN (reviewed by Feng et al [ 136 ]).…”

Section: Integration: the Central Event In Hiv Replicationmentioning

confidence: 99%

The role of integration and clonal expansion in HIV infection: live long and prosper

Anderson¹,

Maldarelli²

2018

Retrovirology

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Integration of viral DNA into the host genome is a central event in the replication cycle and the pathogenesis of retroviruses, including HIV. Although most cells infected with HIV are rapidly eliminated in vivo, HIV also infects long-lived cells that persist during combination antiretroviral therapy (cART). Cells with replication competent HIV proviruses form a reservoir that persists despite cART and such reservoirs are at the center of efforts to eradicate or control infection without cART. The mechanisms of persistence of these chronically infected long-lived cells is uncertain, but recent research has demonstrated that the presence of the HIV provirus has enduring effects on infected cells. Cells with integrated proviruses may persist for many years, undergo clonal expansion, and produce replication competent HIV. Even proviruses with defective genomes can produce HIV RNA and may contribute to ongoing HIV pathogenesis. New analyses of HIV infected cells suggest that over time on cART, there is a shift in the composition of the population of HIV infected cells, with the infected cells that persist over prolonged periods having proviruses integrated in genes associated with regulation of cell growth. In several cases, strong evidence indicates the presence of the provirus in specific genes may determine persistence, proliferation, or both. These data have raised the intriguing possibility that after cART is introduced, a selection process enriches for cells with proviruses integrated in genes associated with cell growth regulation. The dynamic nature of populations of cells infected with HIV during cART is not well understood, but is likely to have a profound influence on the composition of the HIV reservoir with critical consequences for HIV eradication and control strategies. As such, integration studies will shed light on understanding viral persistence and inform eradication and control strategies. Here we review the process of HIV integration, the role that integration plays in persistence, clonal expansion of the HIV reservoir, and highlight current challenges and outstanding questions for future research.

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“…IN is capable of assembling the STC with the product of the concerted integration reaction (a branched viral/target DNA substrate) and the SSC that utilizes only viral DNA substrates in vitro (1)(2)(3)(4)(5)(6). Our results here suggest that the soluble form of the RSV STC may not address what regions or residues of IN are necessary for assembly as well as what is observed with the SSC.…”

Section: Assembly Of Retrovirus Tetrameric and Octameric Intasomesmentioning

confidence: 77%

Differential assembly of Rous sarcoma virus tetrameric and octameric intasomes is regulated by the C-terminal domain and tail region of integrase

Bera

Pandey

Aihara

et al. 2018

Journal of Biological Chemistry

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Retrovirus integrase (IN) catalyzes the concerted integration of linear viral DNA ends into chromosomes. The atomic structures of five different retrovirus IN-DNA complexes, termed intasomes, have revealed varying IN subunit compositions ranging from tetramers to octamers, dodecamers, and hexadecamers. Intasomes containing two IN-associated viral DNA ends capable of concerted integration are termed stable synaptic complexes (SSC), and those formed with a viral/target DNA substrate representing the product of strand-transfer reactions are strand-transfer complexes (STC). Here, we investigated the mechanisms associated with the assembly of the Rous sarcoma virus SSC and STC. C-terminal truncations of WT IN (286 residues) indicated a role of the last 18 residues ("tail" region) in assembly of the tetrameric and octameric SSC, physically stabilized by HIV-1 IN strand-transfer inhibitors. Fine mapping through C-terminal truncations and site-directed mutagenesis suggested that at least three residues (Asp-268-Thr-270) past the last β-strand in the C-terminal domain (CTD) are necessary for assembly of the octameric SSC. In contrast, the assembly of the octameric STC was independent of the last 18 residues of IN. Single-site substitutions in the CTD affected the assembly of the SSC, but not necessarily of the STC, suggesting that STC assembly may depend less on specific interactions of the CTD with viral DNA. Additionally, we demonstrate that trans-communication between IN dimer-DNA complexes facilitates the association of native long-terminal repeat (LTR) ends with partially defective LTR ends to produce a hybrid octameric SSC. The differential assembly of the tetrameric and octameric SSC improves our understanding of intasomes.

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Retroviral intasomes arising

Cited by 47 publications

References 47 publications

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

The role of integration and clonal expansion in HIV infection: live long and prosper

Differential assembly of Rous sarcoma virus tetrameric and octameric intasomes is regulated by the C-terminal domain and tail region of integrase

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