scholarly journals Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors

2015 ◽  
Vol 60 (1) ◽  
pp. 190-197 ◽  
Author(s):  
Emiko Urano ◽  
Sherimay D. Ablan ◽  
Rebecca Mandt ◽  
Gary T. Pauly ◽  
Dina M. Sigano ◽  
...  
Keyword(s):  
Variable Response ◽  
Virus Maturation ◽  
Viral Loads ◽  
Gag Polyprotein ◽  
Alkyl Amine ◽  
Clade B ◽  
Late Step ◽  
Polyprotein Precursor ◽  
Loss Of Susceptibility ◽  
Hiv 1

ABSTRACTConcomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.

scholarly journals Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor

Virology ◽  
2004 ◽  
Vol 328 (2) ◽  
pp. 163-168 ◽  
Author(s):  
Alexandra Schäfer ◽  
Hal P. Bogerd ◽  
Bryan R. Cullen
Keyword(s):  
Gag Polyprotein ◽  
Polyprotein Precursor ◽  
Hiv 1

scholarly journals New Insights into HIV Assembly and Trafficking

Physiology ◽  
2011 ◽  
Vol 26 (4) ◽  
pp. 236-251 ◽  
Author(s):  
Muthukumar Balasubramaniam ◽  
Eric O. Freed
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Biology ◽  
Particle Production ◽  
Virus Assembly ◽  
Gag Polyprotein ◽  
Immunodeficiency Virus ◽  
Cellular Machinery ◽  
Polyprotein Precursor ◽  
Hiv 1

Assembly and release of human immunodeficiency virus type 1 (HIV-1) particles is mediated by the viral Gag polyprotein precursor. Gag is synthesized in the cytosol and rapidly translocates to membrane to orchestrate particle production. The cell biology of HIV-1 Gag trafficking is currently one of the least understood aspects of HIV-1 replication. In this review, we highlight the current understanding of the cellular machinery involved in Gag trafficking and virus assembly.

scholarly journals PF74 and Its Novel Derivatives Stabilize Hexameric Lattice of HIV-1 Mature-Like Particles

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1895
Author(s):  
Alžběta Dostálková ◽  
Kryštof Škach ◽  
Filip Kaufman ◽  
Ivana Křížová ◽  
Romana Hadravová ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Early Stage ◽  
Protein A ◽  
Protein Protein Interactions ◽  
Particle Assembly ◽  
Gag Polyprotein ◽  
Polyprotein Precursor ◽  
Hiv 1 ◽  
Ca Protein

A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part of the Gag polyprotein precursor, facilitates protein–protein interactions that lead to the assembly of immature particles. Following protease activation and Gag polyprotein processing, CA also drives the assembly of the mature viral core. In the early stage of infection, the role of the CA protein is distinct. It controls the disassembly of the mature CA hexameric lattice i.e., uncoating, which is critical for the reverse transcription of the single-stranded RNA genome into double stranded DNA. These properties make CA a very attractive target for small molecule functioning as inhibitors of HIV-1 particle assembly and/or disassembly. Of these, inhibitors containing the PF74 scaffold have been extensively studied. In this study, we reported a series of modifications of the PF74 molecule and its characterization through a combination of biochemical and structural approaches. Our data supported the hypothesis that PF74 stabilizes the mature HIV-1 CA hexameric lattice. We identified derivatives with a higher in vitro stabilization activity in comparison to the original PF74 molecule.

scholarly journals Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa

2010 ◽  
Vol 84 (16) ◽  
pp. 8202-8208 ◽  
Author(s):  
Louis-Marie Yindom ◽  
Aleksandra Leligdowicz ◽  
Maureen P. Martin ◽  
Xiaojiang Gao ◽  
Ying Qi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hla Class I ◽  
Gene Products ◽  
Viral Loads ◽  
Susceptibility To Infection ◽  
Clade B ◽  
Clade C ◽  
Unique Nature ◽  
First Time ◽  
Hiv 1

ABSTRACT Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.

scholarly journals CryoET structures of immature HIV Gag reveal a complete six-helix bundle and stabilizing small molecules distinct from IP6

2020 ◽  
Author(s):  
Luiza Mendonça ◽  
Dapeng Sun ◽  
Jiying Ning ◽  
Jiwei Liu ◽  
Abhay Kotecha ◽  
...  
Keyword(s):  
Small Molecules ◽  
Structural Basis ◽  
Particle Assembly ◽  
Virus Maturation ◽  
Helix Bundle ◽  
Polyprotein Precursor ◽  
Subtomogram Averaging ◽  
Gag Assembly ◽  
Hiv 1

AbstractGag is the major HIV-1 structural polyprotein precursor. The Gag SP1 domain with the last residues of CA have been hypothesized to form a six-helix bundle necessary for particle assembly, but this bundle has not been fully resolved. Here, we determined the structures of complete CA-SP1 six-helix bundle connecting to the NC domain, from both in vitro Gag assemblies and viral-like particles (VLPs) carrying a T8I mutation in SP1, to near-atomic resolutions using cryoET and subtomogram averaging. The structures revealed novel densities, however distinct from IP6, inside the six-helix bundle of Gag assemblies, stabilizing the immature lattice. Interestingly, the T8I mutation impaired proteolytic cleavage of Gag at both SP1 boundaries. Our findings signify the involvement of small molecules in immature Gag assembly and provide the structural basis for development of small molecule inhibitors that stabilize SP1 helix, thus interfere with PR-mediated virus maturation.

scholarly journals Subtype Differences in the Interaction of HIV-1 Matrix with Calmodulin: Implications for Biological Functions

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1294
Author(s):  
Alexej Dick ◽  
Simon Cocklin
Keyword(s):  
Host Cell ◽  
Calcium Binding ◽  
Mutational Analysis ◽  
Interaction Networks ◽  
Cell Physiology ◽  
Gag Polyprotein ◽  
Clade B ◽  
Promising Therapeutic Target ◽  
Clade C ◽  
Hiv 1

The HIV-1 Gag polyprotein plays essential roles during the late stage of the HIV-1 replication cycle, and has recently been identified as a promising therapeutic target. The N-terminal portion of the HIV-1 Gag polyprotein encodes the myristoylated matrix (MA) protein, which functions in the trafficking of the structural proteins to the plasma membrane (PM) and facilitation of envelope incorporation into budding virus. Numerous host cell proteins interact with the MA portion of the Gag polyprotein during this process. One such factor is the ubiquitous calcium-binding protein calmodulin (CaM), which interacts preferentially with myristoylated proteins, thereby regulating cell physiology. The exact role of this interaction is poorly understood to date. Atomic resolution structures revealed the nature of the CaM-MA interaction for clade B isolates. In this study, we expanded our knowledge and characterized biophysically and computationally the CaM interaction with MA from other HIV-1 clades and discovered differences in the CaM recognition as compared to the prototypical clade B MA., with significant alterations in the interaction with the MA protein from clade C. Structural investigation and in silico mutational analysis revealed that HIV-1 MA protein from clade C, which is responsible for the majority of global HIV-1 infections, interacts with lower affinity and altered kinetics as compared to the canonical clade B. This finding may have implications for additional altered interaction networks as compared to the well-studied clade B. Our analysis highlights the importance of expanding investigations of virus-host cell factor interaction networks to other HIV-1 clades.

scholarly journals High-resolution structures of HIV-1 Gag cleavage mutants determine structural switch for virus maturation

2018 ◽  
Vol 115 (40) ◽  
pp. E9401-E9410 ◽  
Author(s):  
Simone Mattei ◽  
Aaron Tan ◽  
Bärbel Glass ◽  
Barbara Müller ◽  
Hans-Georg Kräusslich ◽  
...  
Keyword(s):  
High Resolution ◽  
Virus Maturation ◽  
Helix Bundle ◽  
Gag Polyprotein ◽  
Capsid Formation ◽  
C Terminus ◽  
Beta Hairpin ◽  
Proteolytic Cleavages ◽  
Hairpin Formation ◽  
Hiv 1

HIV-1 maturation occurs via multiple proteolytic cleavages of the Gag polyprotein, causing rearrangement of the virus particle required for infectivity. Cleavage results in beta-hairpin formation at the N terminus of the CA (capsid) protein and loss of a six-helix bundle formed by the C terminus of CA and the neighboring SP1 peptide. How individual cleavages contribute to changes in protein structure and interactions, and how the mature, conical capsid forms, are poorly understood. Here, we employed cryoelectron tomography to determine morphology and high-resolution CA lattice structures for HIV-1 derivatives in which Gag cleavage sites are mutated. These analyses prompt us to revise current models for the crucial maturation switch. Unlike previously proposed, cleavage on either terminus of CA was sufficient, in principle, for lattice maturation, while complete processing was needed for conical capsid formation. We conclude that destabilization of the six-helix bundle, rather than beta-hairpin formation, represents the main determinant of structural maturation.

scholarly journals The Zinc Content of HIV-1 NCp7 Affects Its Selectivity for Packaging Signal and Affinity for Stem-Loop 3

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1922
Author(s):  
Ying Wang ◽  
Chao Guo ◽  
Xing Wang ◽  
Lianmei Xu ◽  
Rui Li ◽  
...  
Keyword(s):  
Rna Binding ◽  
Zinc Content ◽  
Binding Property ◽  
Zinc Ions ◽  
Packaging Signal ◽  
Stem Loop ◽  
Virus Maturation ◽  
Gag Polyprotein ◽  
Zinc Finger Motifs ◽  
Hiv 1

The nucleocapsid (NC) protein of human immunodeficiency (HIV) is a small, highly basic protein containing two CCHC zinc-finger motifs, which is cleaved from the NC domain of the Gag polyprotein during virus maturation. We previously reported that recombinant HIV-1 Gag and NCp7 overexpressed in an E. coli host contains two and one zinc ions, respectively, and Gag exhibited much higher selectivity for packaging signal (Psi) and affinity for the stem-loop (SL)-3 of Psi than NCp7. In this study, we prepared NCp7 containing 0 (0NCp7), 1 (NCp7) or 2 (2NCp7) zinc ions, and compared their secondary structure, Psi-selectivity and SL3-affinity. Along with the decrease of the zinc content, less ordered conformations were detected. Compared to NCp7, 2NCp7 exhibited a much higher Psi-selectivity and SL3-affinity, similar to Gag, whereas 0NCp7 exhibited a lower Psi-selectivity and SL3-affinity, similar to the H23&H44K double mutant of NCp7, indicating that the different RNA-binding property of Gag NC domain and the mature NCp7 may be resulted, at least partially, from their different zinc content. This study will be helpful to elucidate the critical roles that zinc played in the viral life cycle, and benefit further investigations of the functional switch from the NC domain of Gag to the mature NCp7.

Accumulated Mutations Cause Significant Fitness Losses and are Associated with Decreased Viral Loads During Early HIV-1 Infection

2019 ◽  
Author(s):  
Chu Wang ◽  
Donglai Liu ◽  
Tao Zuo ◽  
Bhavna Hora ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Viral Loads ◽  
Hiv 1

Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

2019 ◽  
Vol 17 (5) ◽  
pp. 350-359
Author(s):  
Liliana Acevedo-Saenz ◽  
Federico Perdomo-Celis ◽  
Carlos J. Montoya ◽  
Paula A. Velilla
Keyword(s):  
T Cell ◽  
Reverse Transcriptase ◽  
Cellular Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Cell Responses ◽  
Clade B ◽  
Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

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