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 Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

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.

The balance between p53 isoforms modulates the efficiency of HIV-1 infection in macrophages

2021 ◽  
Author(s):  
Yann Breton ◽  
Corinne Barat ◽  
Michel J. Tremblay
Keyword(s):  
Virus Replication ◽  
Potential Role ◽  
Host Factors ◽  
Fine Tuning ◽  
Mrna Levels ◽  
Cellular Environment ◽  
P53 Isoforms ◽  
Antiviral Role ◽  
Hiv 1

Several host factors influence HIV-1 infection and replication. The p53-mediated antiviral role in monocytes-derived macrophages (MDMs) was previously highlighted. Indeed, an increase in p53 level results in a stronger restriction against HIV-1 early replication steps through SAMHD1 activity. In this study, we investigated the potential role of some p53 isoforms in HIV-1 infection. Transfection of isoform-specific siRNA induces distinctive effects on the virus life cycle. For example, in contrast to a siRNA targeting all isoforms, a knockdown of Δ133p53 transcripts reduces virus replication in MDMs that is correlated with a decrease in phosphorylated inactive SAMHD1. Combination of Δ133p53 knockdown and Nutlin-3, a pharmacological inhibitor of MDM2 that stabilizes p53, further reduces susceptibility of MDMs to HIV-1 infection, thus suggesting an inhibitory role of Δ133p53 towards p53 antiviral activity. In contrast, p53β knockdown in MDMs increases the viral production independently of SAMHD1. Moreover, experiments with a Nef-deficient virus show that this viral protein plays a protective role against the antiviral environment mediated by p53. Finally, HIV-1 infection affects the expression pattern of p53 isoforms by increasing p53β and p53γ mRNA levels while stabilizing the protein level of p53α and some isoforms from the p53β subclass. The balance between the various p53 isoforms is therefore an important factor in the overall susceptibility of macrophages to HIV-1 infection, fine-tuning the p53 response against HIV-1. This study brings a new understanding of the complex role of p53 in virus replication processes in myeloid cells. Importance As of today, HIV-1 is still considered as a global pandemic without a functional cure, partly because of the presence of stable viral reservoirs. Macrophages constitute one of these cell reservoirs, contributing to the viral persistence. Studies investigating the host factors involved in cell susceptibility to HIV-1 infection might lead to a better understanding of the reservoir formation and will eventually allow the development of an efficient cure. Our team previously showed the antiviral role of p53 in macrophages, which acts by compromising the early steps of HIV-1 replication. In this study, we demonstrate the involvement of p53 isoforms, which regulates p53 activity and define the cellular environment influencing viral replication. In addition, the results concerning the potential role of p53 in antiviral innate immunity could be transposed to other fields of virology and suggest that knowledge in oncology can be applied to HIV-1 research.

scholarly journals PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex

2018 ◽  
Vol 93 (6) ◽  
Author(s):  
Muthukumar Balasubramaniam ◽  
Jing Zhou ◽  
Amma Addai ◽  
Phillip Martinez ◽  
Jui Pandhare ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Integrase Inhibitor ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Clear Understanding ◽  
Nuclear Entry ◽  
Preintegration Complex ◽  
Gradient Based ◽  
Hiv 1

ABSTRACTThe HIV-1 capsid protein (CA) facilitates reverse transcription and nuclear entry of the virus. However, CA’s role in post-nuclear entry steps remains speculative. We describe a direct link between CA and integration by employing the capsid inhibitor PF74 as a probe coupled with the biochemical analysis of HIV-1 preintegration complexes (PICs) isolated from acutely infected cells. At a low micromolar concentration, PF74 potently inhibited HIV-1 infection without affecting reverse transcription. Surprisingly, PF74 markedly reduced proviral integration owing to inhibition of nuclear entry and/or integration. However, a 2-fold reduction in nuclear entry by PF74 did not quantitatively correlate with the level of antiviral activity. Titration of PF74 against the integrase inhibitor raltegravir showed an additive antiviral effect that is dependent on a block at the post-nuclear entry step. PF74’s inhibitory effect was not due to the formation of defective viral DNA ends or a delay in integration, suggesting that the compound inhibits PIC-associated integration activity. Unexpectedly, PICs recovered from cells infected in the presence of PF74 exhibited elevated integration activity. PF74’s effect on PIC activity is CA specific since the compound did not increase the integration activity of PICs of a PF74-resistant HIV-1 CA mutant. Sucrose gradient-based fractionation studies revealed that PICs assembled in the presence of PF74 contained lower levels of CA, suggesting a negative association between CA and PIC-associated integration activity. Finally, the addition of a CA-specific antibody or PF74 inhibited PIC-associated integration activity. Collectively, our results demonstrate that PF74’s targeting of PIC-associated CA results in impaired HIV-1 integration.IMPORTANCEAntiretroviral therapy (ART) that uses various combinations of small molecule inhibitors has been highly effective in controlling HIV. However, the drugs used in the ART regimen are expensive, cause side effects, and face viral resistance. The HIV-1 CA plays critical roles in the virus life cycle and is an attractive therapeutic target. While currently there is no CA-based therapy, highly potent CA-specific inhibitors are being developed as a new class of antivirals. Efforts to develop a CA-targeted therapy can be aided through a clear understanding of the role of CA in HIV-1 infection. CA is well established to coordinate reverse transcription and nuclear entry of the virus. However, the role of CA in post-nuclear entry steps of HIV-1 infection is poorly understood. We show that a CA-specific drug PF74 inhibits HIV-1 integration revealing a novel role of this multifunctional viral protein in a post-nuclear entry step of HIV-1 infection.

scholarly journals A Novel Leu92 Mutant of HIV-1 Reverse Transcriptase with a Selective Deficiency in Strand Transfer Causes a Loss of Viral Replication

2015 ◽  
Vol 89 (16) ◽  
pp. 8119-8129 ◽  
Author(s):  
Eytan Herzig ◽  
Nickolay Voronin ◽  
Nataly Kucherenko ◽  
Amnon Hizi
Keyword(s):  
Life Cycle ◽  
Viral Replication ◽  
Reverse Transcriptase ◽  
Dna Polymerase ◽  
Reverse Transcription ◽  
Polymerase Activity ◽  
Rnase H ◽  
Strand Transfer ◽  
Hiv 1

ABSTRACTThe process of reverse transcription (RTN) in retroviruses is essential to the viral life cycle. This key process is catalyzed exclusively by the viral reverse transcriptase (RT) that copies the viral RNA into DNA by its DNA polymerase activity, while concomitantly removing the original RNA template by its RNase H activity. During RTN, the combination between DNA synthesis and RNA hydrolysis leads to strand transfers (or template switches) that are critical for the completion of RTN. The balance between these RT-driven activities was considered to be the sole reason for strand transfers. Nevertheless, we show here that a specific mutation in HIV-1 RT (L92P) that does not affect the DNA polymerase and RNase H activities abolishes strand transfer. There is also a good correlation between this complete loss of the RT's strand transfer to the loss of the DNA clamp activity of the RT, discovered recently by us. This finding indicates a mechanistic linkage between these two functions and that they are both direct and unique functions of the RT (apart from DNA synthesis and RNA degradation). Furthermore, when the RT's L92P mutant was introduced into an infectious HIV-1 clone, it lost viral replication, due to inefficient intracellular strand transfers during RTN, thus supporting thein vitrodata. As far as we know, this is the first report on RT mutants that specifically and directly impair RT-associated strand transfers. Therefore, targeting residue Leu92 may be helpful in selectively blocking this RT activity and consequently HIV-1 infectivity and pathogenesis.IMPORTANCEReverse transcription in retroviruses is essential for the viral life cycle. This multistep process is catalyzed by viral reverse transcriptase, which copies the viral RNA into DNA by its DNA polymerase activity (while concomitantly removing the RNA template by its RNase H activity). The combination and balance between synthesis and hydrolysis lead to strand transfers that are critical for reverse transcription completion. We show here for the first time that a single mutation in HIV-1 reverse transcriptase (L92P) selectively abolishes strand transfers without affecting the enzyme's DNA polymerase and RNase H functions. When this mutation was introduced into an infectious HIV-1 clone, viral replication was lost due to an impaired intracellular strand transfer, thus supporting thein vitrodata. Therefore, finding novel drugs that target HIV-1 reverse transcriptase Leu92 may be beneficial for developing new potent and selective inhibitors of retroviral reverse transcription that will obstruct HIV-1 infectivity.

scholarly journals COVID-19 Docking Server: a meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19

2020 ◽  
Vol 36 (20) ◽  
pp. 5109-5111 ◽  
Author(s):  
Ren Kong ◽  
Guangbo Yang ◽  
Rui Xue ◽  
Ming Liu ◽  
Feng Wang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Drug Discovery ◽  
Small Molecules ◽  
Web Server ◽  
Supplementary Information ◽  
Binding Modes ◽  
Supplementary Data ◽  
Virus Life Cycle ◽  
Ligand Interactions ◽  
New Type

Abstract Motivation The coronavirus disease 2019 (COVID-19) caused by a new type of coronavirus has been emerging from China and led to thousands of death globally since December 2019. Despite many groups have engaged in studying the newly emerged virus and searching for the treatment of COVID-19, the understanding of the COVID-19 target–ligand interactions represents a key challenge. Herein, we introduce COVID-19 Docking Server, a web server that predicts the binding modes between COVID-19 targets and the ligands including small molecules, peptides and antibodies. Results Structures of proteins involved in the virus life cycle were collected or constructed based on the homologs of coronavirus, and prepared ready for docking. The meta-platform provides a free and interactive tool for the prediction of COVID-19 target–ligand interactions and following drug discovery for COVID-19. Availability and implementation http://ncov.schanglab.org.cn. Supplementary information Supplementary data are available at Bioinformatics online.

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.

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