scholarly journals An insight into the Inhibition of HIV‐1 replication by co‐infecting HHV‐6, HHV‐7 or GVB‐C viruses: Role of Mutually Homologous miRNAs in Downregulation of Viral Replication

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Omar Bagasra ◽  
Mayank Aggarwal ◽  
krishna chaitanya Addanki ◽  
Mohammad Alsayari ◽  
samina Noorali ◽  
...  
Keyword(s):  
Viral Replication ◽  
Insight Into ◽  
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 Management of HIV-1 associated hepatitis in patients with acquired immunodeficiency syndrome: role of a successful control of viral replication

2011 ◽  
Vol 8 (1) ◽  
pp. 9 ◽  
Author(s):  
Antonella Esposito ◽  
Valentina Conti ◽  
Maria Cagliuso ◽  
Daniele Pastori ◽  
Alessandra Fantauzzi ◽  
...  
Keyword(s):  
Viral Replication ◽  
Acquired Immunodeficiency Syndrome ◽  
Successful Control ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

scholarly journals Dynamics of HIV-1 Rev sub-nuclear trafficking reveal new insight into the role of RNA in the regulation of Rev nucleolar accumulation

Retrovirology ◽  
2013 ◽  
Vol 10 (S1) ◽  
Author(s):  
Elena Woods ◽  
Jane Courtney ◽  
Annmarie McCartin ◽  
Alessandro Marcello ◽  
William W Hall ◽  
...  
Keyword(s):  
Nuclear Trafficking ◽  
Insight Into ◽  
Hiv 1

scholarly journals Emergence of compensatory mutations reveal the importance of electrostatic interactions between HIV-1 integrase and genomic RNA

2021 ◽  
Author(s):  
Christian Shema Mugisha ◽  
Tung Dinh ◽  
Kasyap Tenneti ◽  
Jenna Eve Eschbach ◽  
Keanu Davis ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Rna Binding ◽  
Class Ii ◽  
Integrase Inhibitors ◽  
Ribonucleoprotein Complexes ◽  
Compensatory Mutations ◽  
Insight Into ◽  
Hiv 1 ◽  
Molecular Nature

Independent of its catalytic activity, HIV-1 integrase (IN) enzyme regulates proper particle maturation by binding to and packaging the viral RNA genome (gRNA) inside the mature capsid lattice. Allosteric integrase inhibitors (ALLINIs) and class II IN substitutions inhibit the binding of IN to the gRNA and cause the formation of non-infectious virions characterized by mislocalization of the viral ribonucleoprotein complexes between the translucent conical capsid lattice and the viral lipid envelope. To gain insight into the molecular nature of IN-gRNA interactions, we have isolated compensatory substitutions in the background of a class II IN (R269A/K273A) variant that directly inhibits IN binding to the gRNA. We found that additional D256N and D270N substitutions in the C-terminal domain (CTD) of IN restored its ability to bind gRNA and led to the formation of infectious particles with correctly matured morphology. Furthermore, reinstating the overall positive electrostatic potential of the CTD through individual D256R or D256K substitutions was sufficient to restore IN-RNA binding and infectivity for the R269A/K273A as well as the R262A/R263A class II IN mutants. The compensatory mutations did not impact functional IN oligomerization, suggesting that they directly contributed to IN binding to the gRNA. Interestingly, HIV-1 IN R269A/K273A, but not IN R262A/R263A, bearing compensatory mutations was more sensitive to ALLINIs providing key genetic evidence that specific IN residues required for RNA binding also influence ALLINI activity. Structural modeling provided further insight into the molecular nature of IN-gRNA interactions and ALLINI mechanism of action. Taken together, our findings highlight an essential role of IN-gRNA interactions for proper virion maturation and reveal the importance of electrostatic interactions between the IN CTD and the gRNA.

scholarly journals Murine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome/Lysosome Pathway to Counteract SERINC5 Antiretroviral Activity

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Sunan Li ◽  
Iqbal Ahmad ◽  
Jing Shi ◽  
Bin Wang ◽  
Changqing Yu ◽  
...  
Keyword(s):  
Steady State ◽  
Viral Replication ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Live Cells ◽  
Receptor Mediated Endocytosis ◽  
Steady State Levels ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACTGlycosylated Gag (glycoGag) is an accessory protein expressed by most gammaretroviruses, including murine leukemia virus (MLV). MLV glycoGag not only enhances MLV replication and disease progression but also increases human immunodeficiency virus type 1 (HIV-1) infectivity as Nef does. Recently, SERINC5 (Ser5) was identified as the target for Nef, and the glycoGag Nef-like activity has been attributed to the Ser5 antagonism. Here, we investigated how glycoGag antagonizes Ser5 using MLV glycoMA and murine Ser5 proteins. We confirm previous observations that glycoMA relocalizes Ser5 from plasma membrane to perinuclear punctated compartments and the important role of its Y36XXL39motif in this process. We find that glycoMA decreases Ser5 expression at steady-state levels and identify two other glycoGag crucial residues, P31 and R63, for the Ser5 downregulation. The glycoMA and Ser5 interaction is detected in live cells using a bimolecular fluorescence complementation assay. Ser5 is internalized via receptor-mediated endocytosis and relocalized to Rab5+early, Rab7+late, and Rab11+recycling endosomes by glycoMA. Although glycoMA is not polyubiquitinated, the Ser5 downregulation requires Ser5 polyubiquitination via the K48- and K63-linkage, resulting in Ser5 destruction in lysosomes. Although P31, Y36, L39, and R63 are not required for glycoMA interaction with Ser5, they are required for Ser5 relocalization to lysosomes for destruction. In addition, although murine Ser1, Ser2, and Ser3 exhibit very poor antiviral activity, they are also targeted by glycoMA for lysosomal destruction. We conclude that glycoGag has a broad activity to downregulate SERINC proteins via the cellular endosome/lysosome pathway, which promotes viral replication.IMPORTANCEMLV glycoGag not only enhances MLV replication but also increases HIV-1 infectivity similarly as Nef. Recent studies have discovered that both glycoGag and Nef antagonize a novel host restriction factor Ser5 and promote viral replication. Compared to Nef, the glycoGag antagonism of Ser5 is still poorly understood. MLV glycoGag is a transmembrane version of the structural Gag protein with an extra 88-amino-acid leader region that determines its activity. We now show that glycoGag interacts with Ser5 in live cells and internalizes Ser5 via receptor-mediated endocytosis. Ser5 is polyubiquitinated and relocalized to endosomes and lysosomes for massive destruction. In addition to the previously identified tyrosine-based sorting signal, we find two more important residues for Ser5 relocalization and downregulation. We also find that the Ser5 sensitivity to glycoGag is conserved in the SERINC family. Together, our findings highlight the important role of endosome/lysosome pathway in the enhancement of viral replication by viral proteins.

scholarly journals Characterization of the Role of Host Cellular Factor Histone Deacetylase 10 during HIV-1 Replication

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 28
Author(s):  
Xiaozhuo Ran ◽  
Zhujun Ao ◽  
Titus Olukitibi ◽  
Xiaojian Yao
Keyword(s):  
Viral Replication ◽  
Histone Deacetylase ◽  
Catalytic Domain ◽  
Inhibitory Factor ◽  
Progeny Virus ◽  
Pcr Analysis ◽  
Transcriptional Level ◽  
Virus Infectivity ◽  
Hiv 1

To date, a series of histone deacetylases have been documented to restrict HIV-1 replication at different steps. In this study, we identified histone deacetylase 10 (HDAC10) as an inhibitory factor against HIV-1 replication. Our results showed that endogenous HDAC10 is downregulated at the transcriptional level during HIV-1 replication. By knocking down HDAC10 in CD4+ T cells with specific shRNAs, we observed that the downregulation of HDAC10 significantly facilitates viral replication. Moreover, RQ-PCR analysis revealed that the downregulation of HDAC10 increased viral integrated DNA. Further, we identified that HDAC10 interacts with the HIV-1 integrase (IN) and that the region of residues from 55 to 165 in the catalytic domain of IN is required for HDAC10 binding. Interestingly, we found that the interaction between HDAC10 and IN specifically decreases the interaction between IN and cellular protein lens epithelium-derived growth factor (LEDGF/p75), which consequently leads to the inhibition of viral integration. In addition, we have investigated the role of HDAC10 in the late stage of viral replication by detecting the infectiousness of progeny virus produced from HDAC10 knockdown cells or HDAC10 overexpressing cells and revealed that the progeny virus infectivity is increased in the HDAC10 downregulated cells, but decreased in the HDAC10 overexpressed cells. Overall, these findings provide evidence that HDAC10 acts as a cellular inhibitory factor at the early and late stages of HIV-1 replication.

scholarly journals HIV-1 Gag recruits oligomeric Vpr via two binding sites in p6, but both mature p6 and Vpr are rapidly lost upon target cell entry

2021 ◽  
Author(s):  
Madushi Wanaguru ◽  
Kate N. Bishop
Keyword(s):  
Viral Replication ◽  
Target Cell ◽  
Binding Sites ◽  
Cell Entry ◽  
Target Cells ◽  
Accessory Protein ◽  
Virus Budding ◽  
Early Replication ◽  
Hiv 1

The p12 region of MLV Gag and the p6 region of HIV-1 Gag contain late-domains required for virus budding. Additionally, the accessory protein Vpr is recruited into HIV particles via p6. Mature p12 is essential for early viral replication events, but the role of mature p6 in early replication is unknown. Using a proviral vector in which the gag and pol reading frames are uncoupled, we have performed the first alanine-scanning mutagenesis screens across p6, to probe its importance for early HIV-1 replication and to further understand its interaction with Vpr. The infectivity of our mutants suggests that, unlike p12, p6 is not important for early viral replication. Consistent with this, we observed that p6 is rapidly lost upon target cell entry in time-course immunoblotting experiments. By analysing Vpr incorporation in p6 mutant virions, we identified that the 15-FRFG-18 and 41-LXXLF-45 motifs previously identified as putative Vpr-binding sites are important for Vpr recruitment, but that the 34-ELY-36 motif also suggested to be a Vpr-binding site is dispensable. Additionally, disrupting Vpr oligomerization together with removing either binding motif in p6 reduced Vpr incorporation ∼25-50-fold more than inhibiting Vpr oligomerization alone and ∼10-25-fold more than deletion of each p6 motif alone, implying that multivalency/avidity is important for the interaction. Interestingly, using immunoblotting and immunofluorescence, we observed that most of Vpr is lost concomitantly with p6 during infection, but that a small fraction remains associated with the viral capsid for several hours. This has implications for the function of Vpr in early replication. Importance The p12 protein of MLV and the p6 protein of HIV-1 are both supplementary Gag cleavage products that carry proline-rich motifs which facilitate virus budding. Importantly, p12 has also been found to be essential for early viral replication events. However, whilst Vpr, the only accessory protein packaged into HIV-1 virions, is recruited via the p6 region of Gag, the function of both mature p6 and Vpr in early replication is unclear. Here, we have systematically mutated the p6 region of gag and have studied the effects on HIV infectivity and Vpr packaging. We have also investigated what happens to p6 and Vpr during early infection. We show that, unlike p12, mature p6 is not required for early replication and that most of the mature p6, and the Vpr that it recruits, are lost rapidly upon target cell entry. This has implications for the role of Vpr in target cells.

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