scholarly journals Impact of Synonymous Genome Recoding on the HIV Life Cycle

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Jordan-Paiz ◽  
Sandra Franco ◽  
Miguel Angel Martínez
Keyword(s):  
Life Cycle ◽  
Large Scale ◽  
Viral Gene Expression ◽  
Virus Genome ◽  
Infection Process ◽  
Replication Capacity ◽  
Viral Gene ◽  
Mutational Robustness ◽  
Synonymous Mutations ◽  
Hiv 1

Synonymous mutations within protein coding regions introduce changes in DNA or messenger (m) RNA, without mutating the encoded proteins. Synonymous recoding of virus genomes has facilitated the identification of previously unknown virus biological features. Moreover, large-scale synonymous recoding of the genome of human immunodeficiency virus type 1 (HIV-1) has elucidated new antiviral mechanisms within the innate immune response, and has improved our knowledge of new functional virus genome structures, the relevance of codon usage for the temporal regulation of viral gene expression, and HIV-1 mutational robustness and adaptability. Continuous improvements in our understanding of the impacts of synonymous substitutions on virus phenotype – coupled with the decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments – have enhanced our ability to identify potential HIV-1 and host factors and other aspects involved in the infection process. In this review, we address how silent mutagenesis impacts HIV-1 phenotype and replication capacity. We also discuss the general potential of synonymous recoding of the HIV-1 genome to elucidate unknown aspects of the virus life cycle, and to identify new therapeutic targets.

scholarly journals The E3 Ubiquitin-Protein Ligase Cullin 3 Regulates HIV-1 Transcription

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2010 ◽  
Author(s):  
Simon Langer ◽  
Xin Yin ◽  
Arturo Diaz ◽  
Alex J. Portillo ◽  
David E. Gordon ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Life Cycle ◽  
Viral Replication ◽  
Viral Gene Expression ◽  
Viral Life Cycle ◽  
Cellular Proteins ◽  
Viral Gene ◽  
Cullin 3 ◽  
Hiv 1

The infectious life cycle of the human immunodeficiency virus type 1 (HIV-1) is characterized by an ongoing battle between a compendium of cellular proteins that either promote or oppose viral replication. On the one hand, HIV-1 utilizes dependency factors to support and sustain infection and complete the viral life cycle. On the other hand, both inducible and constitutively expressed host factors mediate efficient and functionally diverse antiviral processes that counteract an infection. To shed light into the complex interplay between HIV-1 and cellular proteins, we previously performed a targeted siRNA screen to identify and characterize novel regulators of viral replication and identified Cullin 3 (Cul3) as a previously undescribed factor that negatively regulates HIV-1 replication. Cul3 is a component of E3-ubiquitin ligase complexes that target substrates for ubiquitin-dependent proteasomal degradation. In the present study, we show that Cul3 is expressed in HIV-1 target cells, such as CD4+ T cells, monocytes, and macrophages and depletion of Cul3 using siRNA or CRISPR/Cas9 increases HIV-1 infection in immortalized cells and primary CD4+ T cells. Conversely, overexpression of Cul3 reduces HIV-1 infection in single replication cycle assays. Importantly, the antiviral effect of Cul3 was mapped to the transcriptional stage of the viral life cycle, an effect which is independent of its role in regulating the G1/S cell cycle transition. Using isogenic viruses that only differ in their promotor region, we find that the NF-κB/NFAT transcription factor binding sites in the LTR are essential for Cul3-dependent regulation of viral gene expression. Although Cul3 effectively suppresses viral gene expression, HIV-1 does not appear to antagonize the antiviral function of Cul3 by targeting it for degradation. Taken together, these results indicate that Cul3 is a negative regulator of HIV-1 transcription which governs productive viral replication in infected cells.

scholarly journals HIV-1 Protease Evolvability is Affected by Synonymous Nucleotide Recoding

2018 ◽  
Author(s):  
Maria Nevot ◽  
Ana Jordan-Paiz ◽  
Glòria Martrus ◽  
Cristina Andrés ◽  
Damir García-Cehic ◽  
...  
Keyword(s):  
Sequence Space ◽  
Large Scale ◽  
Selective Pressure ◽  
Population Diversity ◽  
Wild Type ◽  
Resistance Mutations ◽  
Mutational Robustness ◽  
Evolutionary Trajectory ◽  
Synonymous Mutations ◽  
Hiv 1

ABSTRACTOne unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair re-engineered protease sequence including 38 (13%) synonymous mutations. WT and MAX viruses showed indistinguishable replication in MT-4 cells or PBMCs. Both viruses were subjected to serial passages in MT-4 cells with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV). After 32 successive passages, both the WT and MAX viruses developed phenotypic resistance to PIs (IC5014.6 ± 5.3 and 21.2 ± 9 nM for ATV, and 5. 9 ± 1.0 and 9.3 ± 1.9 for DRV, respectively). Ultra-deep sequence clonal analysis revealed that both viruses harbored previously described resistance mutations to ATV and DRV. However, the WT and MAX virus proteases showed different resistance variant repertoires, with the G16E and V77I substitutions observed only in WT, and the L33F, S37P, G48L, Q58E/K, and L89I substitutions detected only in MAX. Remarkably, G48L and L89I are rarely foundin vivoin PI-treated patients. The MAX virus showed significantly higher nucleotide and amino acid diversity of the propagated viruses with and without PIs (P< 0.0001), suggesting higher selective pressure for change in this recoded virus. Our results indicate that HIV-1 protease position in sequence space delineates the evolution of its mutant spectra. Nevertheless, the investigated synonymously recoded variant showed mutational robustness and evolvability similar to the WT virus.IMPORTANCELarge-scale synonymous recoding of virus genomes is a new tool for exploring various aspects of virus biology. Synonymous virus genome recoding can be used to investigate how a virus’s position in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenesis. In this study, we evaluated how synonymous recoding of the human immunodeficiency virus type 1 (HIV-1) protease impacts the development of protease inhibitor (PI) resistance. HIV-1 protease is a main target of current antiretroviral therapies. Our present results demonstrate that the wild-type (WT) virus and the virus with the recoded protease exhibited different patterns of resistance mutations after PI treatment. Nevertheless, the developed PI resistance phenotype was indistinguishable between the recoded virus and the WT virus, suggesting that the synonymously recoded protease HIV-1 and the WT protease virus were equally robust and evolvable.

scholarly journals The [KIL-d] Element Specifically Regulates Viral Gene Expression in Yeast

Genetics ◽  
2000 ◽  
Vol 155 (2) ◽  
pp. 601-609 ◽  
Author(s):  
Zsolt Tallóczy ◽  
Rebecca Mazar ◽  
Denise E Georgopoulos ◽  
Fausto Ramos ◽  
Michael J Leibowitz
Keyword(s):  
Gene Expression ◽  
Phenotypic Expression ◽  
Viral Gene Expression ◽  
Virus Genome ◽  
Viral Rna ◽  
High Rate ◽  
Viral Gene ◽  
Double Stranded Rna ◽  
Yeast Prions ◽  
Killer Virus

Abstract The cytoplasmically inherited [KIL-d] element epigenetically regulates killer virus gene expression in Saccharomyces cerevisiae. [KIL-d] results in variegated defects in expression of the M double-stranded RNA viral segment in haploid cells that are “healed” in diploids. We report that the [KIL-d] element is spontaneously lost with a frequency of 10−4–10−5 and reappears with variegated phenotypic expression with a frequency of ≥10−3. This high rate of loss and higher rate of reappearance is unlike any known nucleic acid replicon but resembles the behavior of yeast prions. However, [KIL-d] is distinct from the known yeast prions in its relative guanidinium hydrochloride incurability and independence of Hsp104 protein for its maintenance. Despite its transmissibility by successive cytoplasmic transfers, multiple cytoplasmic nucleic acids have been proven not to carry the [KIL-d] trait. [KIL-d] epigenetically regulates the expression of the M double-stranded RNA satellite virus genome, but fails to alter the expression of M cDNA. This specificity remained even after a cycle of mating and meiosis. Due to its unique genetic properties and viral RNA specificity, [KIL-d] represents a new type of genetic element that interacts with a viral RNA genome.

scholarly journals Fourth NF-κB site in HIV-1 subtype-C LTR confers functional advantage to viral gene expression

Retrovirology ◽  
2009 ◽  
Vol 6 (S2) ◽  
Author(s):  
Mahesh Bachu ◽  
Rajesh V Murali ◽  
Anil MHKH Babu ◽  
Venkat SRK Yedavalli ◽  
Kuan-Teh Jeang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Subtype C ◽  
Functional Advantage ◽  
Hiv 1

scholarly journals Impact of Tat Genetic Variation on HIV-1 Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Luna Li ◽  
Satinder Dahiya ◽  
Sandhya Kortagere ◽  
Benjamas Aiamkitsumrit ◽  
David Cunningham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcriptional Activation ◽  
Viral Gene Expression ◽  
Functional Domains ◽  
Viral Gene ◽  
Molecular Architecture ◽  
Viral Transactivator ◽  
Hiv Drugs ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation withintatof different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability withintatmay impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

scholarly journals 8 Implication of the HIV-1 pol gene intragenic enhancer in myeloid-specific viral gene expression

2017 ◽  
Vol 3 ◽  
pp. 8
Author(s):  
R. Verdikt ◽  
L. Colin ◽  
C. Vanhulle ◽  
B. Van Driessche ◽  
A. Kula ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv 1

Differential viral gene expression and its effect on the biological properties of the cell clones of an HIV-1-infected cell line

Virology ◽  
1990 ◽  
Vol 177 (1) ◽  
pp. 380-383 ◽  
Author(s):  
V.S. Kalyanaraman ◽  
V. Rodriguez ◽  
S. Josephs ◽  
R.C. Gallo ◽  
M.G. Sarngadharan
Keyword(s):  
Gene Expression ◽  
Infected Cell ◽  
Cell Line ◽  
Viral Gene Expression ◽  
Biological Properties ◽  
Viral Gene ◽  
Infected Cell Line ◽  
Cell Clones ◽  
Hiv 1

scholarly journals Epitranscriptomic Addition of m5C to HIV-1 Transcripts Regulates Viral Gene Expression

2019 ◽  
Vol 26 (2) ◽  
pp. 217-227.e6 ◽  
Author(s):  
David G. Courtney ◽  
Kevin Tsai ◽  
Hal P. Bogerd ◽  
Edward M. Kennedy ◽  
Brittany A. Law ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv 1

scholarly journals Highly Divergent Lentiviral Tat Proteins Activate Viral Gene Expression by a Common Mechanism

1999 ◽  
Vol 19 (7) ◽  
pp. 4592-4599 ◽  
Author(s):  
Paul D. Bieniasz ◽  
Therese A. Grdina ◽  
Hal P. Bogerd ◽  
Bryan R. Cullen
Keyword(s):  
Gene Expression ◽  
Protein Complex ◽  
Equine Infectious Anemia Virus ◽  
Viral Gene Expression ◽  
Human Cells ◽  
Common Mechanism ◽  
Viral Gene ◽  
Target Element ◽  
Anemia Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Tat protein (hTat) activates transcription initiated at the viral long terminal repeat (LTR) promoter by a unique mechanism requiring recruitment of the human cyclin T1 (hCycT1) cofactor to the viral TAR RNA target element. While activation of equine infectious anemia virus (EIAV) gene expression by the EIAV Tat (eTat) protein appears similar in that the target element is a promoter proximal RNA, eTat shows little sequence homology to hTat, does not activate the HIV-1 LTR, and is not active in human cells that effectively support hTat function. To address whether eTat and hTat utilize similar or distinct mechanisms of action, we have cloned the equine homolog of hCycT1 (eCycT1) and examined whether it is required to mediate eTat function. Here, we report that expression of eCycT1 in human cells fully rescues eTat function and that eCycT1 and eTat form a protein complex that specifically binds to the EIAV, but not the HIV-1, TAR element. While hCycT1 is also shown to interact with eTat, the lack of eTat function in human cells is explained by the failure of the resultant protein complex to bind to EIAV TAR. Critical sequences in eCycT1 required to support eTat function are located very close to the amino terminus, i.e., distal to the HIV-1 Tat-TAR interaction motif previously identified in the hCycT1 protein. Together, these data provide a molecular explanation for the species tropism displayed by eTat and demonstrate that highly divergent lentiviral Tat proteins activate transcription from their cognate LTR promoters by essentially identical mechanisms.

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