scholarly journals IP6 Regulation of HIV Capsid Assembly, Stability, and Uncoating

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 640 ◽  
Author(s):  
Robert Dick ◽  
Donna Mallery ◽  
Volker Vogt ◽  
Leo James
Keyword(s):  
Replication Cycle ◽  
Capsid Assembly ◽  
Mature Protein ◽  
Inositol Hexakisphosphate ◽  
Cellular Metabolite ◽  
Immature Particle ◽  
Protein Shell ◽  
Hiv 1 ◽  
Positively Charged

The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent discoveries of positively-charged rings in the immature and mature protein hexamer subunits that comprise them and their binding to the cellular metabolite inositol hexakisphosphate (IP6) have stimulated exciting new hypotheses. In this paper, we discuss how data from multiple structural and biochemical approaches are revealing potential roles for IP6 in the HIV-1 replication cycle from assembly to uncoating.

Molecular Docking, Synthesis and anti-HIV-1 Protease Activity of Novel Chalcones

2020 ◽  
Vol 26 (8) ◽  
pp. 802-814 ◽  
Author(s):  
Nemanja Turkovic ◽  
Branka Ivkovic ◽  
Jelena Kotur-Stevuljevic ◽  
Milica Tasic ◽  
Bojan Marković ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Molecular Docking ◽  
Chemical Synthesis ◽  
Protease Activity ◽  
Molecular Mechanisms ◽  
Replication Cycle ◽  
Low Molecular Weight ◽  
Chalcone Derivatives ◽  
Anti Hiv ◽  
Hiv 1

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.

scholarly journals Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5α identified by magic-angle spinning NMR and molecular dynamics simulations

2018 ◽  
Vol 115 (45) ◽  
pp. 11519-11524 ◽  
Author(s):  
Caitlin M. Quinn ◽  
Mingzhang Wang ◽  
Matthew P. Fritz ◽  
Brent Runge ◽  
Jinwoo Ahn ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Building Blocks ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Capsid Assembly ◽  
Dynamic Regulation ◽  
Angle Spinning ◽  
Dynamics Simulations ◽  
Hiv 1

The host factor protein TRIM5α plays an important role in restricting the host range of HIV-1, interfering with the integrity of the HIV-1 capsid. TRIM5 triggers an antiviral innate immune response by functioning as a capsid pattern recognition receptor, although the precise mechanism by which the restriction is imposed is not completely understood. Here we used an integrated magic-angle spinning nuclear magnetic resonance and molecular dynamics simulations approach to characterize, at atomic resolution, the dynamics of the capsid’s hexameric and pentameric building blocks, and the interactions with TRIM5α in the assembled capsid. Our data indicate that assemblies in the presence of the pentameric subunits are more rigid on the microsecond to millisecond timescales than tubes containing only hexamers. This feature may be of key importance for controlling the capsid’s morphology and stability. In addition, we found that TRIM5α binding to capsid induces global rigidification and perturbs key intermolecular interfaces essential for higher-order capsid assembly, with structural and dynamic changes occurring throughout the entire CA polypeptide chain in the assembly, rather than being limited to a specific protein-protein interface. Taken together, our results suggest that TRIM5α uses several mechanisms to destabilize the capsid lattice, ultimately inducing its disassembly. Our findings add to a growing body of work indicating that dynamic allostery plays a pivotal role in capsid assembly and HIV-1 infectivity.

scholarly journals Identification of a Structural Element in HIV-1 Gag Required for Virus Particle Assembly and Maturation

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Mariia Novikova ◽  
Lucas J. Adams ◽  
Juan Fontana ◽  
Anna T. Gres ◽  
Muthukumar Balasubramaniam ◽  
...  
Keyword(s):  
Virus Assembly ◽  
Critical Role ◽  
Replication Cycle ◽  
Structural Defects ◽  
Fold Axis ◽  
Structural Element ◽  
Particle Assembly ◽  
Compensatory Mutations ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTLate in the HIV-1 replication cycle, the viral structural protein Gag is targeted to virus assembly sites at the plasma membrane of infected cells. The capsid (CA) domain of Gag plays a critical role in the formation of the hexameric Gag lattice in the immature virion, and, during particle release, CA is cleaved from the Gag precursor by the viral protease and forms the conical core of the mature virion. A highly conserved Pro-Pro-Ile-Pro (PPIP) motif (CA residues 122 to 125) [PPIP(122–125)] in a loop connecting CA helices 6 and 7 resides at a 3-fold axis formed by neighboring hexamers in the immature Gag lattice. In this study, we characterized the role of this PPIP(122–125) loop in HIV-1 assembly and maturation. While mutations P123A and P125A were relatively well tolerated, mutation of P122 and I124 significantly impaired virus release, caused Gag processing defects, and abolished infectivity. X-ray crystallography indicated that the P122A and I124A mutations induce subtle changes in the structure of the mature CA lattice which were permissive forin vitroassembly of CA tubes. Transmission electron microscopy and cryo-electron tomography demonstrated that the P122A and I124A mutations induce severe structural defects in the immature Gag lattice and abrogate conical core formation. Propagation of the P122A and I124A mutants in T-cell lines led to the selection of compensatory mutations within CA. Our findings demonstrate that the CA PPIP(122–125) loop comprises a structural element critical for the formation of the immature Gag lattice.IMPORTANCECapsid (CA) plays multiple roles in the HIV-1 replication cycle. CA-CA domain interactions are responsible for multimerization of the Gag polyprotein at virus assembly sites, and in the mature virion, CA monomers assemble into a conical core that encapsidates the viral RNA genome. Multiple CA regions that contribute to the assembly and release of HIV-1 particles have been mapped and investigated. Here, we identified and characterized a Pro-rich loop in CA that is important for the formation of the immature Gag lattice. Changes in this region disrupt viral production and abrogate the formation of infectious, mature virions. Propagation of the mutants in culture led to the selection of second-site compensatory mutations within CA. These results expand our knowledge of the assembly and maturation steps in the viral replication cycle and may be relevant for development of antiviral drugs targeting CA.

scholarly journals The HIV-1 Capsid: Assembly and Restriction by TRIM5α

2013 ◽  
Vol 104 (2) ◽  
pp. 12a
Author(s):  
Barbie K. Ganser-Pornillos ◽  
Owen Pornillos ◽  
Viswanathan Chandrasekaran ◽  
Anchi Cheng ◽  
Wesley I. Sundquist ◽  
...  
Keyword(s):  
Capsid Assembly ◽  
Hiv 1

scholarly journals Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly.

2020 ◽  
Author(s):  
Jonathan C. Reed ◽  
Dennis Solas ◽  
Anatoliy Kitaygorodskyy ◽  
Beverly Freeman ◽  
Dylan T. B. Ressler ◽  
...  
Keyword(s):  
Life Cycle ◽  
Virus Production ◽  
Life Cycle Stage ◽  
Multidrug Resistant ◽  
Capsid Assembly ◽  
Resistance Mutations ◽  
Life Cycle Stages ◽  
Human T Cell ◽  
Gag Assembly ◽  
Hiv 1

Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages not targeted by drugs currently in use. Host-targeting compounds are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, an HIV-1 life cycle stage for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed upon parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that form during immature HIV-1 capsid assembly. Indeed, imaging of infected cells shows compound colocalized with two host enzymes found in assembly intermediates, ABCE1 and DDX6, but not two host proteins found in other complexes. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly. IMPORTANCE The success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations, likely by acting on assembly. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly. However, resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype represents a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

scholarly journals Solution NMR Investigation of HIV-1 Replication Cycle

2020 ◽  
Vol 118 (3) ◽  
pp. 518a-519a
Author(s):  
Bhargavi Ramaraju ◽  
Lalit Deshmukh
Keyword(s):  
Replication Cycle ◽  
Solution Nmr ◽  
Hiv 1

scholarly journals Variants in Host Viral Replication Cycle Genes Are Associated With Heterosexual HIV-1 Acquisition in Africans

2014 ◽  
Vol 66 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Abigail W. Bigham ◽  
Romel D. Mackelprang ◽  
Connie Celum ◽  
Guy De Bruyn ◽  
Kristin Beima-Sofie ◽  
...  
Keyword(s):  
Viral Replication ◽  
Replication Cycle ◽  
Hiv 1

The pH dependence of HIV-1 capsid assembly and its interaction with cyclophilin A

2003 ◽  
Vol 105 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Marjorie BonHomme ◽  
Stanislaus Wong ◽  
Carol Carter ◽  
Suzanne Scarlata
Keyword(s):  
Ph Dependence ◽  
Cyclophilin A ◽  
Capsid Assembly ◽  
Hiv 1
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