scholarly journals gp120 Alters Its Conformation to Enhance Evasiveness and Infectivity

2021 ◽  
Author(s):  
Joseph A. Ayariga ◽  
Logan Gildea ◽  
Ayodeji Ipimoroti ◽  
Qiana L. Matthews
Keyword(s):  
Structural Dynamics ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Host Immunity ◽  
Viral Envelope ◽  
Cell Surface Receptor ◽  
Type I ◽  
Structural Constraints ◽  
Conformational States ◽  
Hiv 1

Infection by human immunodeficiency virus type I (HIV-1) requires virus particle binding to host cell-surface receptor CD4 via the viral envelope glycoprotein gp120. HIV-1 therapy and prevention efforts involve development of mimetic or recombinant gp120 vaccines or deployment of antiviral agents that target specific epitopes of gp120. The unliganded conformational state of gp120 is closed, whereas the CD4-bound state is open. However, in between, there exist dynamic conformational states, indicating intrinsically flexible region(s) of structural dynamics, imposing a structural challenge for developing drug or antibody targets. Known conformational states of gp120 were determined by X-ray crystallographic and cryo-electron microscopy, and neither method captures the population of gp120 species arising from conformational plasticity, motions, and transitions. gp120 plasticity brings up several important questions. How will differences in conformation affect receptor binding, antibody recognition, and neutralization? Which regions are crucial for gp120 structural plasticity? How could structural dynamics influence HIV-1 evasiveness against host immunity and drugs or vaccines, and facilitate the viral entry into its host? This review explores the structural constraints presented by conformational states of the glycoprotein to antibodies or drugs and how these conformational states provide structural avenues for the virus to escape neutralizing agents and evade host immunity.

scholarly journals Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100

2008 ◽  
Vol 82 (23) ◽  
pp. 11695-11704 ◽  
Author(s):  
Jessamina E. Harrison ◽  
Jonathan B. Lynch ◽  
Luz-Jeannette Sierra ◽  
Leslie A. Blackburn ◽  
Neelanjana Ray ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiviral Agents ◽  
Viral Envelope ◽  
Cxcr4 Antagonist ◽  
Immunodeficiency Virus ◽  
Env Protein ◽  
Hiv 1

ABSTRACT We screened a panel of R5X4 and X4 human immunodeficiency virus type 1 (HIV-1) strains for their sensitivities to AMD3100, a small-molecule CXCR4 antagonist that blocks HIV-1 infection via this coreceptor. While no longer under clinical development, AMD3100 is a useful tool with which to probe interactions between the viral envelope (Env) protein and CXCR4 and to identify pathways by which HIV-1 may become resistant to this class of antiviral agents. While infection by most virus strains was completely blocked by AMD3100, we identified several R5X4 and X4 isolates that exhibited plateau effects: as the AMD3100 concentration was increased, virus infection and membrane fusion diminished to variable degrees. Once saturating concentrations of AMD3100 were achieved, further inhibition was not observed, indicating a noncompetitive mode of viral resistance to the drug. The magnitude of the plateau varied depending on the virus isolate, as well as the cell type used, with considerable variation observed when primary human T cells from different human donors were used. Structure-function studies indicated that the V1/V2 region of the R5X4 HIV-1 isolate DH12 was necessary for AMD3100 resistance and could confer this property on two heterologous Env proteins. We conclude that some R5X4 and X4 HIV-1 isolates can utilize the AMD3100-bound conformation of CXCR4, with the efficiency being influenced by both viral and host factors. Baseline resistance to this CXCR4 antagonist could influence the clinical use of such compounds.

scholarly journals Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Jérémie Decalf ◽  
Marion Desdouits ◽  
Vasco Rodrigues ◽  
François-Xavier Gobert ◽  
Matteo Gentili ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Viral Entry ◽  
Reverse Transcription ◽  
Great Part ◽  
Interferon Response ◽  
Viral Reservoir ◽  
Type I ◽  
Viral Fusion ◽  
Viral Spread ◽  
Hiv 1

ABSTRACT Along with CD4+ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection. IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection.

scholarly journals The broad anti-viral agent glycyrrhizin directly modulates the fluidity of plasma membrane and HIV-1 envelope

2005 ◽  
Vol 392 (1) ◽  
pp. 191-199 ◽  
Author(s):  
Shinji Harada
Keyword(s):  
Plasma Membrane ◽  
Membrane Fluidity ◽  
Viral Envelope ◽  
Cell Entry ◽  
Cell Leukaemia ◽  
Fusion Pore ◽  
Type I ◽  
Viral Agent ◽  
Leukaemia Virus ◽  
Hiv 1

Cell entry of enveloped viruses requires a wide-fusion-pore mechanism, involving clustering of fusion-activated proteins and fluidization of the plasma membrane and viral envelope. In the present study, GL (glycyrrhizin) is reported to lower membrane fluidity, thus suppressing infection by HIV, influenza A virus and vesicular stomatitis virus, but not by poliovirus. GL-treated HIV-1 particles showed reduced infectivity. GL also inhibited cell-to-cell fusion induced by HIV-1 and HTLV-I (human T-cell leukaemia virus type I). However, when cells treated with 1 mg/ml GL were placed in GL-free medium, they showed increased susceptibility to HIV-1 infection and HTLV-I fusion due to enhancement of membrane fluidity. The membrane dependence of GL and GL removal experiments suggest that GL does affect the cell entry of viruses. HIVs with more gp120 were less dependent on temperature and less sensitive to GL treatment than those with less gp120, indicating that the existence of more gp120 molecules resulted in a higher probability of forming a cluster of fusion-activated proteins.

scholarly journals Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

2019 ◽  
Author(s):  
Ross D. Overacker ◽  
Somdev Banerjee ◽  
George F. Neuhaus ◽  
Selena Milicevic Sephton ◽  
Alexander Herrmann ◽  
...  
Keyword(s):  
Viral Entry ◽  
Antiviral Agents ◽  
Biological Evaluation ◽  
Rnase H ◽  
Synthetic Compounds ◽  
Infectivity Assay ◽  
Antiviral Compounds ◽  
Specific Manner ◽  
Drug Leads ◽  
Hiv 1

AbstractInspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a singleround infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOLB#24), which exhibited low-micromolar activity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated that azaBINOLB#24acts after viral entry but before viral assembly and budding. HIV-1 reverse transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to demonstrate thatB#24inhibits RNase H activity, most likely allosterically. Further binding analysis using bio-layer interferometry (BLI) showed thatB#24interacts with HIV-1 RT in a highly specific manner. These results indicate that azaBINOLB#24is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.

scholarly journals SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry

2022 ◽  
Vol 119 (4) ◽  
pp. e2117576119
Author(s):  
Bo Yang ◽  
Yuanyuan Jia ◽  
Yumin Meng ◽  
Ying Xue ◽  
Kefang Liu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Viral Entry ◽  
Complex Structure ◽  
Pdz Domain ◽  
Late Endosome ◽  
Endocytic Pathway ◽  
Cell Surface Receptor ◽  
Binding Motif ◽  
Type I

After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27–retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.

scholarly journals Does the Cytoplasmic Tail Matter? Mechanism of Viral Envelope Glycoprotein Targeting by Membrane-Associated-RING-CH (MARCH) Proteins

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 21
Author(s):  
Cheng man Lun ◽  
Abdul A. Waheed ◽  
Eric O. Freed
Keyword(s):  
Antiviral Activity ◽  
Envelope Glycoprotein ◽  
Protein Targeting ◽  
Viral Envelope ◽  
Surface Proteins ◽  
Type I Interferons ◽  
Type I ◽  
Endogenous Expression ◽  
Viral Glycoproteins ◽  
Hiv 1

The MARCH family of RING-finger E3 ubiquitin ligases comprise 11 members that have been reported to play a variety of roles in the downregulation of cell-surface proteins involved in adaptive immunity. The RING-CH domain of MARCH proteins is thought to ubiquitinate the cytoplasmic tails (CTs) of target proteins, leading to protein degradation through either lysosomal or proteasomal pathways. Three MARCH proteins (MARCH1, 2, and 8) have recently been reported to target the HIV-1 envelope glycoprotein (Env) and vesicular stomatitis virus G glycoprotein (VSV-G), thereby impairing the infectivity of HIV-1 virions bearing HIV-1 Env or VSV-G. However, the mechanism of antiviral activity remains poorly defined. Our data show that MARCH proteins antagonize the full-length forms of HIV-1 Env, VSV-G, and Ebola glycoprotein (GP), and impair the infectivity of HIV-1 virions bearing these viral glycoproteins. This Env-targeting activity of the MARCH proteins requires the E3 ubiquitin ligase activity of the RING-CH domain. We observe that the MARCH protein targeting of VSV-G is, to a large extent, CT-dependent. In striking contrast, the MARCH-protein targeting of HIV-1 Env and Ebola GP does not require the CT. Confocal microscopy data demonstrate that MARCH proteins are able to trap the viral glycoproteins in an intracellular compartment. We observe that the endogenous expression of MARCH8 in T-cell lines and PBMCs is inducible by type I interferons (a and b) and is also upregulated by HIV-1 infection. Current studies are aimed at identifying the cellular target for MARCH-mediated ubiquitination in the context of their antiviral activity. These results will clarify the mechanism by which MARCH proteins antagonize viral glycoproteins and provide insights into the antiviral role of cellular inhibitory factors in Env biogenesis, trafficking, and virion incorporation.

scholarly journals HIV-1 Envelope Glycoprotein at the Interface of Host Restriction and Virus Evasion

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 311 ◽  
Author(s):  
Saina Beitari ◽  
Yimeng Wang ◽  
Shan-Lu Liu ◽  
Chen Liang
Keyword(s):  
Viral Infection ◽  
Adaptive Immunity ◽  
Viral Entry ◽  
Envelope Protein ◽  
Envelope Proteins ◽  
Viral Envelope ◽  
Innate Immune ◽  
Host Restriction ◽  
Hiv 1 ◽  
Viral Envelope Proteins

Without viral envelope proteins, viruses cannot enter cells to start infection. As the major viral proteins present on the surface of virions, viral envelope proteins are a prominent target of the host immune system in preventing and ultimately eliminating viral infection. In addition to the well-appreciated adaptive immunity that produces envelope protein-specific antibodies and T cell responses, recent studies have begun to unveil a rich layer of host innate immune mechanisms restricting viral entry. This review focuses on the exciting progress that has been made in this new direction of research, by discussing various known examples of host restriction of viral entry, and diverse viral countering strategies, in particular, the emerging role of viral envelope proteins in evading host innate immune suppression. We will also highlight the effective cooperation between innate and adaptive immunity to achieve the synergistic control of viral infection by targeting viral envelope protein and checking viral escape. Given that many of the related findings were made with HIV-1, we will use HIV-1 as the model virus to illustrate the basic principles and molecular mechanisms on host restriction targeting HIV-1 envelope protein.

scholarly journals Low pH Is Required for Avian Sarcoma and Leukosis Virus Env-Dependent Viral Penetration into the Cytosol and Not for Viral Uncoating

2004 ◽  
Vol 78 (19) ◽  
pp. 10433-10441 ◽  
Author(s):  
Richard J. O. Barnard ◽  
Shakti Narayan ◽  
Geethanjali Dornadula ◽  
Michael D. Miller ◽  
John A. T. Young
Keyword(s):  
Viral Entry ◽  
Strong Support ◽  
Low Ph ◽  
Viral Envelope ◽  
Specific Cell ◽  
Dependent Manner ◽  
Surface Receptors ◽  
Ph Dependent ◽  
Avian Sarcoma ◽  
Hiv 1

ABSTRACT A novel entry mechanism has been proposed for the avian sarcoma and leukosis virus (ASLV), whereby interaction with specific cell surface receptors activates or primes the viral envelope glycoprotein (Env), rendering it sensitive to subsequent low-pH-dependent fusion triggering in acidic intracellular organelles. However, ASLV fusion seems to proceed to a lipid mixing stage at neutral pH, leading to the suggestion that low pH might instead be required for a later stage of viral entry such as uncoating (L. J. Earp, S. E. Delos, R. C. Netter, P. Bates, and J. M. White. J. Virol. 77:3058-3066, 2003). To address this possibility, hybrid virus particles were generated with the core of human immunodeficiency virus type 1 (HIV-1), a known pH-independent virus, and with subgroups A or B ASLV Env proteins. Infection of cells by these pseudotyped virions was blocked by lysosomotropic agents, as judged by inhibition of HIV-1 DNA synthesis. Furthermore, by using HIV-1 cores that contain a Vpr-β-lactamase fusion protein (Vpr-BlaM) to monitor viral penetration into the cytosol, we demonstrated that virions bearing ASLV Env, but not HIV-1 Env, enter the cytosol in a low-pH-dependent manner. This effect was independent of the presence of the cytoplasmic tail of ASLV Env. These studies provide strong support for the model, indicating that low pH is required for ASLV Env-dependent viral penetration into the cytosol and not for viral uncoating.

scholarly journals In vitro Activity of a Novel Series of Polyoxosilicotungstates against Human Myxo-, Herpes- and Retroviruses

1993 ◽  
Vol 4 (5) ◽  
pp. 253-262 ◽  
Author(s):  
S. Ikeda ◽  
J. Neyts ◽  
N. Yamamoto ◽  
B. Murrer ◽  
B. Theobald ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Virus Type ◽  
Viral Envelope ◽  
Cell Surface Receptor ◽  
Virus Adsorption ◽  
Hiv 1 ◽  
Hsv 1

A series of silicon-containing polyoxotungstates belonging to the ‘Keggin-type’ (‘Keggin’, ‘Keggin sandwich’) were evaluated for their antiviral activity against enveloped viruses (myxo-, herpes- and retroviruses). The compounds exhibited antiviral activity against influenza virus type A, respiratory syncytial virus (RSV), herpes simplex virus type-1 (HSV-1), type-2 (HSV-2), thymidine kinase-deficient (TIC) HSV-1, human cytomegalovirus (HCMV), human immunodeficiency virus type-1 (HIV-1) and type-2 (HIV-2) at concentrations that were well below their cytotoxic threshold. The ‘Keggin’ compound JM2815 (K5[Si-(TiCp)W11O39].12H2O) and the ‘Keggin sandwich’ compound JM1590 (K13[Ce(SiW11O39)2].26H2O) resulted in the highest selectivity indices against HIV-1 and HIV-2, and compound JM2820 ([Me3NH]8.[Si2Nb6W18O77]) was the most potent inhibitor of HSV and HCMV replication. These compounds proved active against HCMV and HSV when present during virus adsorption, and against influenza virus A and RSV when present after virus adsorption. Polyoxosilicotungstates inhibited the binding of radiolabeled HCMV particles to the cells at concentrations that were antivirally active, and the compounds were able to displace HCMV particles that were bound to a heparin-Sepharose matrix. Presumably, the polyoxosilicotungstates interact with positively charged domains on the viral envelope site(s) involved in the attachment of the (HCMV) virions to the cell surface receptor heparan sulphate.

scholarly journals Imaging Viral Infection by Fluorescence Microscopy: Focus on HIV-1 Early Stage

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 213
Author(s):  
Soumajit Mukherjee ◽  
Emmanuel Boutant ◽  
Eleonore Réal ◽  
Yves Mély ◽  
Halina Anton
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Integration Site ◽  
Viral Envelope ◽  
Integration Step ◽  
Imaging Studies ◽  
Cytoplasmic Transport ◽  
Capsid Shell ◽  
Wide Range ◽  
Hiv 1

During the last two decades, progresses in bioimaging and the development of various strategies to fluorescently label the viral components opened a wide range of possibilities to visualize the early phase of Human Immunodeficiency Virus 1 (HIV-1) life cycle directly in infected cells. After fusion of the viral envelope with the cell membrane, the viral core is released into the cytoplasm and the viral RNA (vRNA) is retro-transcribed into DNA by the reverse transcriptase. During this process, the RNA-based viral complex transforms into a pre-integration complex (PIC), composed of the viral genomic DNA (vDNA) coated with viral and host cellular proteins. The protective capsid shell disassembles during a process called uncoating. The viral genome is transported into the cell nucleus and integrates into the host cell chromatin. Unlike biochemical approaches that provide global data about the whole population of viral particles, imaging techniques enable following individual viruses on a single particle level. In this context, quantitative microscopy has brought original data shedding light on the dynamics of the viral entry into the host cell, the cytoplasmic transport, the nuclear import, and the selection of the integration site. In parallel, multi-color imaging studies have elucidated the mechanism of action of host cell factors implicated in HIV-1 viral cycle progression. In this review, we describe the labeling strategies used for HIV-1 fluorescence imaging and report on the main advancements that imaging studies have brought in the understanding of the infection mechanisms from the viral entry into the host cell until the provirus integration step.

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