scholarly journals Cellular Cofactors of Lentiviral Integrase: From Target Validation to Drug Discovery

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Oliver Taltynov ◽  
Belete A. Desimmie ◽  
Jonas Demeulemeester ◽  
Frauke Christ ◽  
Zeger Debyser
Keyword(s):  
Small Molecules ◽  
Host Cell ◽  
Nuclear Import ◽  
Viral Proteins ◽  
Binding Pocket ◽  
Host Proteins ◽  
Lentiviral Infection ◽  
Antiviral Targets ◽  
Cell Chromosome ◽  
Hiv 1

To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

Viral gene products and replication of the human immunodeficiency type 1 virus

1994 ◽  
Vol 266 (5) ◽  
pp. C1135-C1156 ◽  
Author(s):  
C. D. Morrow ◽  
J. Park ◽  
J. K. Wakefield
Keyword(s):  
Host Cell ◽  
Early Phase ◽  
Viral Genome ◽  
Social Issues ◽  
Late Phase ◽  
Viral Proteins ◽  
Cell Surface Receptor ◽  
Rna Genome ◽  
Cell Chromosome ◽  
Hiv 1

The acquired immunodeficiency syndrome (AIDS) epidemic represents a modern-day plague that has not only resulted in a tragic loss of people from a wide spectrum of society but has reshaped our viewpoints regarding health care, the treatment of infectious diseases, and social issues regarding sexual behavior. There is little doubt now that the cause of the disease AIDS is a virus known as the human immunodeficiency virus (HIV). The HIV virus is a member of a large family of viruses termed retroviruses, which have as a hallmark the capacity to convert their RNA genome into a DNA form that then undergoes a process of integration into the host cell chromosome, followed by the expression of the viral genome and translation of viral proteins in the infected cell. This review describes the organization of the HIV-1 viral genome, the expression of viral proteins, as well as the functions of the accessory viral proteins in HIV replication. The replication of the viral genome is divided into two phases, the early phase and the late phase. The early phase consists of the interaction of the virus with the cell surface receptor (CD4 molecule in most cases), the uncoating and conversion of the viral RNA genome into a DNA form, and the integration into the host cell chromosome. The late phase consists of the expression of the viral proteins from the integrated viral genome, the translation of viral proteins, and the assembly and release of the virus. Points in the HIV-1 life cycle that are targets for therapeutic intervention are also discussed.

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 Uncovering potential host proteins and pathways that may interact with eukaryotic short linear motifs in viral proteins of MERS, SARS and SARS2 coronaviruses that infect humans

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246150
Author(s):  
Chu-Wen Yang ◽  
Zhi-Ling Shi
Keyword(s):  
Host Cell ◽  
Virus Replication ◽  
Viral Infections ◽  
Viral Proteins ◽  
Host Cells ◽  
Host Proteins ◽  
Cell Components ◽  
Linear Motifs ◽  
Novel Coronavirus ◽  
High Possibility

A coronavirus pandemic caused by a novel coronavirus (SARS-CoV-2) has spread rapidly worldwide since December 2019. Improved understanding and new strategies to cope with novel coronaviruses are urgently needed. Viruses (especially RNA viruses) encode a limited number and size (length of polypeptide chain) of viral proteins and must interact with the host cell components to control (hijack) the host cell machinery. To achieve this goal, the extensive mimicry of SLiMs in host proteins provides an effective strategy. However, little is known regarding SLiMs in coronavirus proteins and their potential targets in host cells. The objective of this study is to uncover SLiMs in coronavirus proteins that are present within host cells. These SLiMs have a high possibility of interacting with host intracellular proteins and hijacking the host cell machinery for virus replication and dissemination. In total, 1,479 SLiM hits were identified in the 16 proteins of 590 coronaviruses infecting humans. Overall, 106 host proteins were identified that may interact with SLiMs in 16 coronavirus proteins. These SLiM-interacting proteins are composed of many intracellular key regulators, such as receptors, transcription factors and kinases, and may have important contributions to virus replication, immune evasion and viral pathogenesis. A total of 209 pathways containing proteins that may interact with SLiMs in coronavirus proteins were identified. This study uncovers potential mechanisms by which coronaviruses hijack the host cell machinery. These results provide potential therapeutic targets for viral infections.

scholarly journals HIV-1 Nef targets calnexin: a novel mechanism behind Nef effects on host cell and viral proteins

Retrovirology ◽  
2013 ◽  
Vol 10 (S1) ◽  
Author(s):  
Lucas Jennelle ◽  
Ruth Hunegnaw ◽  
Dmitri Sviridov ◽  
Michael Bukrinsky
Keyword(s):  
Host Cell ◽  
Viral Proteins ◽  
Hiv 1

scholarly journals A SARS-CoV-2 – host proximity interactome

2020 ◽  
Author(s):  
Payman Samavarchi-Tehrani ◽  
Hala Abdouni ◽  
James D.R. Knight ◽  
Audrey Astori ◽  
Reuben Samson ◽  
...  
Keyword(s):  
Host Cell ◽  
Protein Interactions ◽  
Affinity Purification ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Host Protein ◽  
Virus Protein ◽  
Host Proteins ◽  
Biochemical Purification ◽  
Cell Functions

AbstractViral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.

scholarly journals Complex Interplay between HIV-1 Capsid and MX2-Independent Alpha Interferon-Induced Antiviral Factors

2016 ◽  
Vol 90 (16) ◽  
pp. 7469-7480 ◽  
Author(s):  
Lorenzo Bulli ◽  
Luis Apolonia ◽  
Juliane Kutzner ◽  
Darja Pollpeter ◽  
Caroline Goujon ◽  
...  
Keyword(s):  
Host Cell ◽  
Reverse Transcription ◽  
Nuclear Import ◽  
Type I Interferons ◽  
Wild Type Virus ◽  
Type I ◽  
Wild Type ◽  
Complex Interplay ◽  
Hiv 1 ◽  
Effector Mechanisms

ABSTRACTType I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4+T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.IMPORTANCEHIV-1 is the causative agent of AIDS. During acute HIV-1 infection, numerous proinflammatory cytokines are produced, including type I interferons (IFNs). IFNs can limit HIV-1 replication by inducing the expression of a set of antiviral genes that inhibit HIV-1 at multiple steps in its life cycle, including the postentry steps of reverse transcription and nuclear import. This is observed in cultured cell systems, as well as in clinical trials in HIV-1-infected patients. The identities of the cellular antiviral factors, their viral targets, and the underpinning mechanisms are largely unknown. We show here that the HIV-1 Capsid protein plays a central role in protecting the virus from IFN-induced inhibitors that block early postentry steps of infection. We further show that host cell cyclophilins play an important role in regulating these processes, thus highlighting the complex interplay between antiviral effector mechanisms and viral survival.

scholarly journals The Role of Capsid in the Early Steps of HIV-1 Infection: New Insights into the Core of the Matter

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1161
Author(s):  
Nawal Al Burtamani ◽  
Alwin Paul ◽  
Ariberto Fassati
Keyword(s):  
Life Cycle ◽  
Small Molecules ◽  
Reverse Transcription ◽  
Nuclear Import ◽  
Protein A ◽  
Host Factors ◽  
Virus Life Cycle ◽  
Experimental Approaches ◽  
Hiv 1

In recent years, major advances in research and experimental approaches have significantly increased our knowledge on the role of the HIV-1 capsid in the virus life cycle, from reverse transcription to integration and gene expression. This makes the capsid protein a good pharmacological target to inhibit HIV-1 replication. This review covers our current understanding of the role of the viral capsid in the HIV-1 life cycle and its interaction with different host factors that enable reverse transcription, trafficking towards the nucleus, nuclear import and integration into host chromosomes. It also describes different promising small molecules, some of them in clinical trials, as potential targets for HIV-1 therapy.

scholarly journals Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Ke Peng ◽  
Walter Muranyi ◽  
Bärbel Glass ◽  
Vibor Laketa ◽  
Stephen R Yant ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Nuclear Import ◽  
Viral Proteins ◽  
Host Factors ◽  
Quantitative Detection ◽  
Quantitative Microscopy ◽  
Nuclear Entry ◽  
High Concentrations ◽  
Post Entry ◽  
Hiv 1

The steps from HIV-1 cytoplasmic entry until integration of the reverse transcribed genome are currently enigmatic. They occur in ill-defined reverse-transcription- and pre-integration-complexes (RTC, PIC) with various host and viral proteins implicated. In this study, we report quantitative detection of functional RTC/PIC by labeling nascent DNA combined with detection of viral integrase. We show that the viral CA (capsid) protein remains associated with cytoplasmic RTC/PIC but is lost on nuclear PIC in a HeLa-derived cell line. In contrast, nuclear PIC were almost always CA-positive in primary human macrophages, indicating nuclear import of capsids or capsid-like structures. We further show that the CA-targeted inhibitor PF74 exhibits a bimodal mechanism, blocking RTC/PIC association with the host factor CPSF6 and nuclear entry at low, and abrogating reverse transcription at high concentrations. The newly developed system is ideally suited for studying retroviral post-entry events and the roles of host factors including DNA sensors and signaling molecules.

scholarly journals Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2369
Author(s):  
Heidy Elkhaligy ◽  
Christian A. Balbin ◽  
Jessica L. Gonzalez ◽  
Teresa Liberatore ◽  
Jessica Siltberg-Liberles
Keyword(s):  
Host Cell ◽  
Interaction Network ◽  
Viral Proteins ◽  
Amino Acid Residues ◽  
Host Proteins ◽  
Protein Surfaces ◽  
Human Virus ◽  
Mechanism Of Interaction ◽  
Virus Interactions ◽  
Enzyme Functions

Most viruses have small genomes that encode proteins needed to perform essential enzymatic functions. Across virus families, primary enzyme functions are under functional constraint; however, secondary functions mediated by exposed protein surfaces that promote interactions with the host proteins may be less constrained. Viruses often form transient interactions with host proteins through conformationally flexible interfaces. Exposed flexible amino acid residues are known to evolve rapidly suggesting that secondary functions may generate diverse interaction potentials between viruses within the same viral family. One mechanism of interaction is viral mimicry through short linear motifs (SLiMs) that act as functional signatures in host proteins. Viral SLiMs display specific patterns of adjacent amino acids that resemble their host SLiMs and may occur by chance numerous times in viral proteins due to mutational and selective processes. Through mimicry of SLiMs in the host cell proteome, viruses can interfere with the protein interaction network of the host and utilize the host-cell machinery to their benefit. The overlap between rapidly evolving protein regions and the location of functionally critical SLiMs suggest that these motifs and their functional potential may be rapidly rewired causing variation in pathogenicity, infectivity, and virulence of related viruses. The following review provides an overview of known viral SLiMs with select examples of their role in the life cycle of a virus, and a discussion of the structural properties of experimentally validated SLiMs highlighting that a large portion of known viral SLiMs are devoid of predicted intrinsic disorder based on the viral SLiMs from the ELM database.

HIV-1 nuclear import: in search of a leader; update 1999

1999 ◽  
Vol 4 (1-3) ◽  
pp. d772 ◽  
Author(s):  
Michael, I. Bukrinsky
Keyword(s):  
Nuclear Import ◽  
Hiv 1
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