scholarly journals TRIM34 acts with TRIM5 to restrict HIV and SIV capsids

2019 ◽  
Author(s):  
Molly Ohainle ◽  
Kyusik Kim ◽  
Sevnur Keceli ◽  
Abby Felton ◽  
Ed Campbell ◽  
...  
Keyword(s):  
Host Cell ◽  
Critical Role ◽  
Restriction Factor ◽  
Target Cells ◽  
Restriction Factors ◽  
Host Proteins ◽  
Hiv Replication ◽  
Cytoplasmic Bodies ◽  
Host Cell Factors ◽  
Hiv 1

AbstractThe HIV-1 capsid protein makes up the core of the virion and plays a critical role in early steps of HIV replication. Due to its exposure in the cytoplasm after entry, HIV capsid is a target for host cell factors that act directly to block infection such as TRIM5 and MxB. Several host proteins also play a role in facilitating infection, including in the protection of HIV-1 capsid from recognition by host cell restriction factors. Through an unbiased screening approach, called HIV-CRISPR, we show that the Cyclophilin A-binding deficient P90A HIV-1 capsid mutant becomes highly-sensitized to TRIM5alpha restriction in IFN-treated cells. Further, the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the well-characterized HIV restriction factor TRIM5. This restriction occurs at the step of reverse transcription, is independent of interferon stimulation and limits HIV-1 infection in key target cells of HIV infection including CD4+ T cells and monocyte-derived dendritic cells. TRIM34 restriction requires TRIM5alpha as knockout or knockdown of TRIM5alpha results in a loss of antiviral activity. TRIM34 can also restrict some SIV capsids. Through immunofluorescence studies, we show that TRIM34 and TRIM5alpha colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with WT capsids. Our results identify TRIM34 as an HIV-1 CA-targeting restriction factor and highlight the potential role for heteromultimeric TRIM interactions in contributing restriction of HIV-1 infection in human cells.

scholarly journals Cellular and Biochemical Mechanisms of the Retroviral Restriction Factor SAMHD1

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Li Wu
Keyword(s):  
Host Protein ◽  
Nucleic Acid Metabolism ◽  
Target Cells ◽  
Restriction Factors ◽  
Host Proteins ◽  
Retroviral Infection ◽  
Deoxynucleoside Triphosphate ◽  
Biochemical Mechanisms ◽  
Hiv 1

Replication of HIV-1 and other retroviruses is dependent on numerous host proteins in the cells. Some of the host proteins, however, function as restriction factors to block retroviral infection of target cells. The host protein SAMHD1 has been identified as the first mammalian deoxynucleoside triphosphate triphosphohydrolase (dNTPase), which blocks the infection of HIV-1 and other retroviruses in non-cycling immune cells. SAMHD1 protein is highly expressed in human myeloid-lineage cells and CD4+ T-lymphocytes, but its retroviral restriction function is only observed in noncycling cells. Recent studies have revealed biochemical mechanisms of SAMHD1-mediated retroviral restriction. In this review, the latest progress on SAMHD1 research is summarized and the mechanisms by which SAMHD1 mediates retroviral restriction are analyzed. Although the physiological function of SAMHD1 is largely unknown, this review provides perspectives about the role of endogenous SAMHD1 protein in maintaining normal cellular function, such as nucleic acid metabolism and the proliferation of cells.

scholarly journals HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 852
Author(s):  
Ashley Lauren Bennett ◽  
Rory Henderson
Keyword(s):  
Host Cell ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Cell Receptor ◽  
Broadly Neutralizing Antibodies ◽  
Structural Mapping ◽  
Host Cell Receptor ◽  
Immunogen Design ◽  
Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 100
Author(s):  
Eric Rossi ◽  
Megan E. Meuser ◽  
Camille J. Cunanan ◽  
Simon Cocklin
Keyword(s):  
Life Cycle ◽  
Capsid Protein ◽  
Adaptor Proteins ◽  
Restriction Factors ◽  
Gag Polyprotein ◽  
Immunodeficiency Virus ◽  
Host Cell Factors ◽  
Hiv 1

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.

scholarly journals Functional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Romain Appourchaux ◽  
Mathilde Delpeuch ◽  
Li Zhong ◽  
Julien Burlaud-Gaillard ◽  
Kevin Tartour ◽  
...  
Keyword(s):  
Target Cell ◽  
Transmembrane Protein ◽  
Regulatory Role ◽  
Target Cells ◽  
Restriction Factors ◽  
Cell Protection ◽  
Differential Behavior ◽  
Antiviral Activities ◽  
Divergent Behavior ◽  
Hiv 1

ABSTRACT The interferon-induced transmembrane proteins (IFITMs) are a family of highly related antiviral factors that affect numerous viruses at two steps: in target cells by sequestering incoming viruses in endosomes and in producing cells by leading to the production of virions that package IFITMs and exhibit decreased infectivity. While most studies have focused on the former, little is known about the regulation of the negative imprinting of virion particle infectivity by IFITMs and about its relationship with target cell protection. Using a panel of IFITM3 mutants against HIV-1, we have explored these issues as well as others related to the biology of IFITM3, in particular virion packaging, stability, the relation to CD63/multivesicular bodies (MVBs), the modulation of cholesterol levels, and the relationship between negative imprinting of virions and target cell protection. The results that we have obtained exclude a role for cholesterol and indicate that CD63 accumulation does not directly relate to an antiviral behavior. We have defined regions that modulate the two antiviral properties of IFITM3 as well as novel domains that modulate protein stability and that, in so doing, influence the extent of its packaging into virions. The results that we have obtained, however, indicate that, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for negative imprinting. Finally, while most mutations concomitantly affect target cell protection and negative imprinting, a region in the C-terminal domain (CTD) exhibits a differential behavior, potentially highlighting the regulatory role that this domain may play in the two antiviral activities of IFITM3. IMPORTANCE IFITM proteins have been associated with the sequestration of incoming virions in endosomes (target cell protection) and with the production of virion particles that incorporate IFITMs and exhibit decreased infectivity (negative imprinting of virion infectivity). How the latter is regulated and whether these two antiviral properties are related remain unknown. By examining the behavior of a large panel of IFITM3 mutants against HIV-1, we determined that IFITM3 mutants are essentially packaged into virions proportionally to their intracellular levels of expression. However, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for the antiviral effects. Most mutations were found to concomitantly affect both antiviral properties of IFITM3, but one CTD mutant exhibited a divergent behavior, possibly highlighting a novel regulatory role for this domain. These findings thus advance our comprehension of how this class of broad antiviral restriction factors acts.

scholarly journals HIV envelope tail truncation confers resistance to SERINC5 restriction

2021 ◽  
Vol 118 (21) ◽  
pp. e2101450118
Author(s):  
Tafhima Haider ◽  
Xenia Snetkov ◽  
Clare Jolly
Keyword(s):  
T Cells ◽  
Envelope Glycoprotein ◽  
Cytoplasmic Tail ◽  
Restriction Factor ◽  
Viral Fusion ◽  
Restriction Factors ◽  
Complete Resistance ◽  
Hiv Envelope ◽  
Hiv 1

SERINC5 is a potent lentiviral restriction factor that gets incorporated into nascent virions and inhibits viral fusion and infectivity. The envelope glycoprotein (Env) is a key determinant for SERINC restriction, but many aspects of this relationship remain incompletely understood, and the mechanism of SERINC5 restriction remains unresolved. Here, we have used mutants of HIV-1 and HIV-2 to show that truncation of the Env cytoplasmic tail (ΔCT) confers complete resistance of both viruses to SERINC5 and SERINC3 restriction. Critically, fusion of HIV-1 ΔCT virus was not inhibited by SERINC5 incorporation into virions, providing a mechanism to explain how EnvCT truncation allows escape from restriction. Neutralization and inhibitor assays showed ΔCT viruses have an altered Env conformation and fusion kinetics, suggesting that EnvCT truncation dysregulates the processivity of entry, in turn allowing Env to escape targeting by SERINC5. Furthermore, HIV-1 and HIV-2 ΔCT viruses were also resistant to IFITMs, another entry-targeting family of restriction factors. Notably, while the EnvCT is essential for Env incorporation into HIV-1 virions and spreading infection in T cells, HIV-2 does not require the EnvCT. Here, we reveal a mechanism by which human lentiviruses can evade two potent Env-targeting restriction factors but show key differences in the capacity of HIV-1 and HIV-2 to exploit this. Taken together, this study provides insights into the interplay between HIV and entry-targeting restriction factors, revealing viral plasticity toward mechanisms of escape and a key role for the long lentiviral EnvCT in regulating these processes.

scholarly journals Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1005 ◽  
Author(s):  
Jennifer L. Elliott ◽  
Sebla B. Kutluay
Keyword(s):  
Life Cycle ◽  
Viral Genome ◽  
Critical Role ◽  
Viral Rna ◽  
Target Cells ◽  
Host Chromosome ◽  
Virion Morphogenesis ◽  
Rna Genome ◽  
Hiv 1

The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of IN has been well studied, and the knowledge gained has informed the design of small molecule inhibitors that now form key components of antiretroviral therapy regimens. Recent discoveries unveiled that IN has an under-studied yet equally vital second function in human immunodeficiency virus type 1 (HIV-1) replication. This involves IN binding to the viral RNA genome in virions, which is necessary for proper virion maturation and morphogenesis. Inhibition of IN binding to the viral RNA genome results in mislocalization of the viral genome inside the virus particle, and its premature exposure and degradation in target cells. The roles of IN in integration and virion morphogenesis share a number of common elements, including interaction with viral nucleic acids and assembly of higher-order IN multimers. Herein we describe these two functions of IN within the context of the HIV-1 life cycle, how IN binding to the viral genome is coordinated by the major structural protein, Gag, and discuss the value of targeting the second role of IN in virion morphogenesis.

scholarly journals The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles

2017 ◽  
Vol 292 (33) ◽  
pp. 13702-13713 ◽  
Author(s):  
Birthe Trautz ◽  
Hannah Wiedemann ◽  
Christian Lüchtenborg ◽  
Virginia Pierini ◽  
Jan Kranich ◽  
...  
Keyword(s):  
Host Cell ◽  
Lipid Composition ◽  
Restriction Factor ◽  
Viral Particles ◽  
Hiv 1

scholarly journals Antiviral Activity and Adaptive Evolution of Avian Tetherins

2020 ◽  
Vol 94 (12) ◽  
Author(s):  
Veronika Krchlíková ◽  
Helena Fábryová ◽  
Tomáš Hron ◽  
Janet M. Young ◽  
Anna Koslová ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Recent Work ◽  
Avian Species ◽  
Domestic Chicken ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Zoonotic Infections ◽  
Avian Viruses ◽  
Avian Sarcoma ◽  
Hiv 1

ABSTRACT Tetherin/BST-2 is an antiviral protein that blocks the release of enveloped viral particles by linking them to the membrane of producing cells. At first, BST-2 genes were described only in humans and other mammals. Recent work identified BST-2 orthologs in nonmammalian vertebrates, including birds. Here, we identify the BST-2 sequence in domestic chicken (Gallus gallus) for the first time and demonstrate its activity against avian sarcoma and leukosis virus (ASLV). We generated a BST-2 knockout in chicken cells and showed that BST-2 is a major determinant of an interferon-induced block of ASLV release. Ectopic expression of chicken BST-2 blocks the release of ASLV in chicken cells and of human immunodeficiency virus type 1 (HIV-1) in human cells. Using metabolic labeling and pulse-chase analysis of HIV-1 Gag proteins, we verified that chicken BST-2 blocks the virus at the release stage. Furthermore, we describe BST-2 orthologs in multiple avian species from 12 avian orders. Previously, some of these species were reported to lack BST-2, highlighting the difficulty of identifying sequences of this extremely variable gene. We analyzed BST-2 genes in the avian orders Galliformes and Passeriformes and showed that they evolve under positive selection. This indicates that avian BST-2 is involved in host-virus evolutionary arms races and suggests that BST-2 antagonists exist in some avian viruses. In summary, we show that chicken BST-2 has the potential to act as a restriction factor against ASLV. Characterizing the interaction of avian BST-2 with avian viruses is important in understanding innate antiviral defenses in birds. IMPORTANCE Birds are important hosts of viruses that have the potential to cause zoonotic infections in humans. However, only a few antiviral genes (called viral restriction factors) have been described in birds, mostly because birds lack counterparts of highly studied mammalian restriction factors. Tetherin/BST-2 is a restriction factor, originally described in humans, that blocks the release of newly formed virus particles from infected cells. Recent work identified BST-2 in nonmammalian vertebrate species, including birds. Here, we report the BST-2 sequence in domestic chicken and describe its antiviral activity against a prototypical avian retrovirus, avian sarcoma and leukosis virus (ASLV). We also identify BST-2 genes in multiple avian species and show that they evolve rapidly in birds, which is an important indication of their relevance for antiviral defense. Analysis of avian BST-2 genes will shed light on defense mechanisms against avian viral pathogens.

scholarly journals The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates

2016 ◽  
Vol 90 (18) ◽  
pp. 8085-8089 ◽  
Author(s):  
Ben Murrell ◽  
Thomas Vollbrecht ◽  
John Guatelli ◽  
Joel O. Wertheim
Keyword(s):  
Viral Infections ◽  
Arms Race ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Arms Races ◽  
Host Restriction ◽  
Host Restriction Factor ◽  
Novel Host ◽  
Evolutionary Arms Race ◽  
Hiv 1

ABSTRACTMolecular evolutionary arms races between viruses and their hosts are important drivers of adaptation. These Red Queen dynamics have been frequently observed in primate retroviruses and their antagonists, host restriction factor genes, such as APOBEC3F/G, TRIM5-α, SAMHD1, and BST-2. Host restriction factors have experienced some of the most intense and pervasive adaptive evolution documented in primates. Recently, two novel host factors, SERINC3 and SERINC5, were identified as the targets of HIV-1 Nef, a protein crucial for the optimal infectivity of virus particles. Here, we compared the evolutionary fingerprints of SERINC3 and SERINC5 to those of other primate restriction factors and to a set of other genes with diverse functions. SERINC genes evolved in a manner distinct from the canonical arms race dynamics seen in the other restriction factors. Despite their antiviral activity against HIV-1 and other retroviruses, SERINC3 and SERINC5 have a relatively uneventful evolutionary history in primates.IMPORTANCERestriction factors are host proteins that block viral infection and replication. Many viruses, like HIV-1 and related retroviruses, evolved accessory proteins to counteract these restriction factors. The importance of these interactions is evidenced by the intense adaptive selection pressures that dominate the evolutionary histories of both the host and viral genes involved in this so-called arms race. The dynamics of these arms races can point to mechanisms by which these viral infections can be prevented. Two human genes, SERINC3 and SERINC5, were recently identified as targets of an HIV-1 accessory protein important for viral infectivity. Unexpectedly, we found that these SERINC genes, unlike other host restriction factor genes, show no evidence of a recent evolutionary arms race with viral pathogens.

scholarly journals S2 from Equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3

2016 ◽  
Author(s):  
Ajit Chande ◽  
Cristiana Cuccurullo ◽  
Annachiara Rosa ◽  
Serena Ziglio ◽  
Susan Carpenter ◽  
...  
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Critical Role ◽  
Host Factor ◽  
Target Cells ◽  
Accessory Protein ◽  
Post Translational Modification ◽  
Virus Particles ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Hiv 1

ABSTRACTThe lentivirus equine infectious anemia virus (EIAV) encodes S2, a pathogenic determinant important for virus replication and disease progression in horses. No molecular function has yet been linked to this accessory protein. We now report that S2 can replace the activity of Nef on HIV-1 infectivity, being required to antagonize the inhibitory activity of SERINC proteins on Nef-defective HIV-1. Similar to Nef, S2 excludes SERINC5 from virus particles and requires an ExxxLL motif predicted to recruit the clathrin adaptor AP2. Accordingly, a functional endocytic machinery is essential for S2-mediated infectivity enhancement, which is impaired by inhibitors of clathrin-mediated endocytosis. In addition to retargeting SERINC5 to a late endosomal compartment, S2 promotes the host factor degradation. Emphasizing the similarity with Nef, we show that S2 is myristoylated and, compatible with a crucial role of the post-translational modification, its N-terminal glycine is required for the anti-SERINC5 activity.EIAV-derived vectors devoid of S2 are less susceptible than HIV-1 to the inhibitory effect of both human and equine SERINC5. We then identified the envelope glycoprotein of EIAV as a determinant which also modulates retrovirus susceptibility to SERINC5, indicating a bi-modular ability of the equine lentivirus to counteract the host factor.S2 shares no sequence homology with other retroviral factors known to counteract SERINC5. Adding to primate lentivirus Nef and gammaretrovirus glycoGag, the accessory protein from EIAV makes another example of a retroviral virulence determinant which independently evolved SERINC5-antagonizing activity. SERINC5 therefore plays a critical role for the interaction of the host with diverse retrovirus pathogens.Significance StatementSERINC5 and SERINC3 are recently discovered cellular inhibitors of retroviruses, which are incorporated into virus particles and impair their ability to propagate the infection to target cells. Only two groups of viruses (represented by HIV-1 and MLV) have so far been identified to have evolved the ability of counteracting SERINC inhibition. We now discovered that Equine infectious anemia virus, which causes a debilitating disease in horses, also acquired the ability to protect the virus particle from inhibition by SERINC5 and SERINC3, using its small protein S2. The evidence that three different retroviruses have independently evolved the ability to elude inhibition bySERINC5 and SERINC3 indicates that these cellular factors play a fundamental role against various retrovirus pathogens.

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