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.

Restricted HIV-1 infection of human astrocytes: potential role of nef in the regulation of virus replication

1998 ◽  
Vol 4 (4) ◽  
pp. 377-386 ◽  
Author(s):  
Paul Gorry ◽  
Damian Purcell ◽  
Jane Howard ◽  
Dale Mcphee
Keyword(s):  
Virus Replication ◽  
Potential Role ◽  
Human Astrocytes ◽  
Hiv 1

scholarly journals Specificity of the HIV-1 Protease on Substrates Representing the Cleavage Site in the Proximal Zinc-Finger of HIV-1 Nucleocapsid Protein

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1092
Author(s):  
János András Mótyán ◽  
Márió Miczi ◽  
Stephen Oroszlan ◽  
József Tőzsér
Keyword(s):  
Amino Acid ◽  
Zinc Finger ◽  
Cleavage Site ◽  
Potential Role ◽  
Binding Mode ◽  
Interaction Energies ◽  
Vitro Assay ◽  
Hiv 1

To explore the sequence context-dependent nature of the human immunodeficiency virus type 1 (HIV-1) protease’s specificity and to provide a rationale for viral mutagenesis to study the potential role of the nucleocapsid (NC) processing in HIV-1 replication, synthetic oligopeptide substrates representing the wild-type and modified versions of the proximal cleavage site of HIV-1 NC were assayed as substrates of the HIV-1 protease (PR). The S1′ substrate binding site of HIV-1 PR was studied by an in vitro assay using KIVKCF↓NCGK decapeptides having amino acid substitutions of N17 residue of the cleavage site of the first zinc-finger domain, and in silico calculations were also performed to investigate amino acid preferences of S1′ site. Second site substitutions have also been designed to produce “revertant” substrates and convert a non-hydrolysable sequence (having glycine in place of N17) to a substrate. The specificity constants obtained for peptides containing non-charged P1′ substitutions correlated well with the residue volume, while the correlation with the calculated interaction energies showed the importance of hydrophobicity: interaction energies with polar residues were related to substantially lower specificity constants. Cleavable “revertants” showed one residue shift of cleavage position due to an alternative productive binding mode, and surprisingly, a double cleavage of a substrate was also observed. The results revealed the importance of alternative binding possibilities of substrates into the HIV-1 PR. The introduction of the “revertant” mutations into infectious virus clones may provide further insights into the potential role of NC processing in the early phase of the viral life-cycle.

scholarly journals Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

2017 ◽  
Vol 15 (5) ◽  
pp. 421-423 ◽  
Author(s):  
Juan Ambrosioni ◽  
Mayte Coiras ◽  
José Alcamí ◽  
José M. Miró
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Potential Role ◽  
Kinase Inhibitors ◽  
Hiv 1

Constitutive RNA synthesis for the yeast activator ADR1 and identification of the ADR1-5c mutation: implications in posttranslational control of ADR1

1986 ◽  
Vol 6 (11) ◽  
pp. 4026-4030
Author(s):  
C L Denis ◽  
C Gallo
Keyword(s):  
Rna Synthesis ◽  
Potential Role ◽  
Glucose Repression ◽  
Posttranslational Regulation ◽  
Mrna Levels ◽  
Recognition Sequence ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Kinase Phosphorylation

The regulation of mRNA production for the yeast positive activator ADR1, a gene required for the expression of the glucose-repressible alcohol dehydrogenase (ADH II), was studied. ADR1 mRNA levels did not vary when yeasts were switched from glucose- to ethanol-containing medium, while ADH II expression increased 100-fold. The mRNA for the ADR1-5c allele, which augments ADH II expression 60-fold during glucose repression, was not present in greater abundance than ADR1 mRNA. Additionally, the ccr1-1 allele, which blocks ADH2 mRNA formation and partially suppresses the ADR1-5c phenotype, did not alter the levels of ADR1 mRNA. These results indicate that ADR1 is not transcriptionally controlled. To determine the character of the ADR1-5c mutation, the region containing the mutation was identified and sequenced. At base pair +683 a G-to-A transition was detected in the ADR1 coding sequence which would result in the substitution of a lysine residue for an arginine at amino acid 228. The location of the ADR1-5c mutation in the interior of the ADR1 coding sequences suggests that it enhances the activity of an extant but inactive ADR1 protein rather than increases the abundance of ADR1 by altered translation of its mRNA. The ADR1-5c mutation occurs in a region of the polypeptide corresponding to a cyclic AMP-dependent protein kinase phosphorylation recognition sequence. The potential role of reversible phosphorylation in the posttranslational regulation of ADR1 is discussed.

scholarly journals Constitutive RNA synthesis for the yeast activator ADR1 and identification of the ADR1-5c mutation: implications in posttranslational control of ADR1.

1986 ◽  
Vol 6 (11) ◽  
pp. 4026-4030 ◽  
Author(s):  
C L Denis ◽  
C Gallo
Keyword(s):  
Rna Synthesis ◽  
Potential Role ◽  
Glucose Repression ◽  
Posttranslational Regulation ◽  
Mrna Levels ◽  
Recognition Sequence ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Kinase Phosphorylation

The regulation of mRNA production for the yeast positive activator ADR1, a gene required for the expression of the glucose-repressible alcohol dehydrogenase (ADH II), was studied. ADR1 mRNA levels did not vary when yeasts were switched from glucose- to ethanol-containing medium, while ADH II expression increased 100-fold. The mRNA for the ADR1-5c allele, which augments ADH II expression 60-fold during glucose repression, was not present in greater abundance than ADR1 mRNA. Additionally, the ccr1-1 allele, which blocks ADH2 mRNA formation and partially suppresses the ADR1-5c phenotype, did not alter the levels of ADR1 mRNA. These results indicate that ADR1 is not transcriptionally controlled. To determine the character of the ADR1-5c mutation, the region containing the mutation was identified and sequenced. At base pair +683 a G-to-A transition was detected in the ADR1 coding sequence which would result in the substitution of a lysine residue for an arginine at amino acid 228. The location of the ADR1-5c mutation in the interior of the ADR1 coding sequences suggests that it enhances the activity of an extant but inactive ADR1 protein rather than increases the abundance of ADR1 by altered translation of its mRNA. The ADR1-5c mutation occurs in a region of the polypeptide corresponding to a cyclic AMP-dependent protein kinase phosphorylation recognition sequence. The potential role of reversible phosphorylation in the posttranslational regulation of ADR1 is discussed.

scholarly journals The Potential Role of HIV-1 Vper Interaction with a Protein Kinase VIP4D1 in Vpr-induced Cell Cycle G2 Arrest 911

1998 ◽  
Vol 43 ◽  
pp. 157-157
Author(s):  
Delane Shingadia ◽  
Jian Cao ◽  
Mingzhong Chen ◽  
Chen Wang ◽  
Yuqi Zhao
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Potential Role ◽  
G2 Arrest ◽  
Hiv 1

scholarly journals Effect of alpha-1 antitrypsin Portland variant (α1-PDX) on HIV-1 replication

2000 ◽  
Vol 352 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Bouchaib BAHBOUHI ◽  
Mourad BENDJENNAT ◽  
Denise GUÉTARD ◽  
Nabil Georges SEIDAH ◽  
Elmostafa BAHRAOUI
Keyword(s):  
Viral Replication ◽  
Potential Role ◽  
Serine Proteinase ◽  
Recombinant Vaccinia Virus ◽  
Jurkat Cells ◽  
Serine Proteinase Inhibitor ◽  
Cdna Insert ◽  
Alpha 1 Antitrypsin ◽  
Hiv 1

The present work investigated the potential role of alpha-1 antitrypsin Portland variant (α1-PDX), a bioengineered serine proteinase inhibitor (serpin), in the interference with the viral replication of HIV-1, induction of syncytia and maturation of envelope glycoprotein gp160 to gp120 and gp41. A Jurkat lymphoid cell line transfected with a plasmid containing the α1-PDX cDNA (J-PDX) and expressing the protein in a stable manner was infected with HIV-1Lai. Controls were Jurkat cells transfected with the same vector pcDNA3 without the cDNA insert (J-pcDNA3). The results showed that viral replication of HIV-1 was significantly inhibited with a delay in replication kinetics in J-PDX cells as compared with J-pcDNA3 cells. In addition, a comparison of the infectious capacity of viruses produced in the presence and absence of α1-PDX revealed that this capacity differed. It was found that α1-PDX exerts its effect by interfering with the formation of syncytia between J-PDX cells infected with gp160 recombinant vaccinia virus, or after infection by HIV-1 and co-culture with uninfected Molt-4 cells. In contrast, when the same experiments were performed with J-pcDNA3 cells, a large number of syncytia was obtained. Analysis of viral proteins by Western blotting and densitometry showed that the inhibition of the cytopathic effect of HIV-1 and viral replication was correlated with the capacity of α1-PDX to interfere with the maturation of gp160 to gp120 and gp41.

scholarly journals Structure–functional analysis of human immunodeficiency virus type 1 (HIV-1) Vpr: role of leucine residues on Vpr-mediated transactivation and virus replication

Virology ◽  
2004 ◽  
Vol 328 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Dineshkumar Thotala ◽  
Elizabeth A. Schafer ◽  
Biswanath Majumder ◽  
Michelle L. Janket ◽  
Marc Wagner ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Human Immunodeficiency Virus ◽  
Virus Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

scholarly journals Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis

Catalysts ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 684
Author(s):  
S. Kashif Sadiq
Keyword(s):  
Cleavage Site ◽  
Catalytic Effect ◽  
Reaction Rates ◽  
Fine Tuning ◽  
Sequence Specificity ◽  
Peptide Hydrolysis ◽  
Multiple Substrates ◽  
Uncatalyzed Reaction ◽  
Hiv 1

The catalytic role of near attack conformations (NACs), molecular states that lie on the pathway between the ground state (GS) and transition state (TS) of a chemical reaction, is not understood completely. Using a computational approach that combines Bürgi–Dunitz theory with all-atom molecular dynamics simulations, the role of NACs in catalyzing the first stages of HIV-1 protease peptide hydrolysis was previously investigated using a substrate that represents the recognized SP1-NC cleavage site of the HIV-1 Gag polyprotein. NACs were found to confer no catalytic effect over the uncatalyzed reaction there ( Δ Δ G N ‡ ∼ 0 kcal/mol). Here, using the same approach, the role of NACs across multiple substrates that each represent a further recognized cleavage site is investigated. Overall rate enhancement varies by | Δ Δ G ‡ | ∼ 12–15 kcal/mol across this set, and although NACs contribute a small and approximately constant barrier to the uncatalyzed reaction (< Δ G N ‡ u > = 4.3 ± 0.3 kcal/mol), they are found to contribute little significant catalytic effect ( | Δ Δ G N ‡ | ∼ 0–2 kcal/mol). Furthermore, no correlation is exhibited between NAC contributions and the overall energy barrier ( R 2 = 0.01). However, these small differences in catalyzed NAC contributions enable rates to match those required for the kinetic order of processing. Therefore, NACs may offer an alternative and subtle mode compared to non-NAC contributions for fine-tuning reaction rates during complex evolutionary sequence selection processes—in this case across cleavable polyproteins whose constituents exhibit multiple functions during the virus life-cycle.

scholarly journals Ceramide Suppresses Influenza A Virus Replication In Vitro

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Nadia Soudani ◽  
Rouba Hage-Sleiman ◽  
Walid Karam ◽  
Ghassan Dbaibo ◽  
Hassan Zaraket
Keyword(s):  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
De Novo ◽  
Dependent Manner ◽  
Biosynthesis Pathway ◽  
Influenza A H1n1 ◽  
Ceramide Accumulation ◽  
Antiviral Role

ABSTRACT Annual influenza outbreaks are associated with significant morbidity and mortality worldwide despite the availability of seasonal vaccines. Influenza pathogenesis depends on the manipulation of host cell signaling to promote virus replication. Ceramide is a sphingosine-derived lipid that regulates diverse cellular processes. Studies highlighted the differential role of ceramide de novo biosynthesis on the propagation of various viruses. Whether ceramide plays, a role in influenza virus replication is not known. In this study, we assessed the potential interplay between the influenza A (IAV) and ceramide biosynthesis pathways. The accumulation of ceramide in human lung epithelial cells infected with influenza A/H1N1 virus strains was evaluated using thin-layer chromatography and/or confocal microscopy. Virus replication was assessed upon the regulation of the de novo ceramide biosynthesis pathway. A significant increase in ceramide accumulation was observed in cells infected with IAV in a dose- and time-dependent manner. Inoculating the cells with UV-inactivated IAV did not result in ceramide accumulation in the cells, suggesting that the induction of ceramide required an active virus replication. Inhibiting de novo ceramide significantly decreased ceramide accumulation and enhanced virus replication. The addition of exogenous C6-ceramide prior to infection mediated an increase in cellular ceramide levels and significantly attenuated IAV replication and reduced viral titers (≈1 log10 PFU/ml unit). Therefore, our data demonstrate that ceramide accumulation through de novo biosynthesis pathway plays a protective and antiviral role against IAV infection. These findings propose new avenues for development of antiviral molecules and strategies. IMPORTANCE Understanding the effect of sphingolipid metabolism on viral pathogenesis provide important insights into the development of therapeutic strategies against microbial infections. In this study, we demonstrate a critical role of ceramide during influenza A virus infection. We demonstrate that ceramide produced through de novo biosynthesis possess an antiviral role. These observations unlock new opportunities for the development of novel antiviral therapies against influenza.

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