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Keywords = non-retroviral integration

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17 pages, 2194 KiB  
Article
Long Terminal Repeats of Gammaretroviruses Retain Stable Expression after Integration Retargeting
by Dalibor Miklík, Martina Slavková, Dana Kučerová, Chahrazed Mekadim, Jakub Mrázek and Jiří Hejnar
Viruses 2024, 16(10), 1518; https://doi.org/10.3390/v16101518 - 25 Sep 2024
Cited by 1 | Viewed by 957
Abstract
Retroviruses integrate into the genomes of infected host cells to form proviruses, a genetic platform for stable viral gene expression. Epigenetic silencing can, however, hamper proviral transcriptional activity. As gammaretroviruses (γRVs) preferentially integrate into active promoter and enhancer sites, the high transcriptional activity [...] Read more.
Retroviruses integrate into the genomes of infected host cells to form proviruses, a genetic platform for stable viral gene expression. Epigenetic silencing can, however, hamper proviral transcriptional activity. As gammaretroviruses (γRVs) preferentially integrate into active promoter and enhancer sites, the high transcriptional activity of γRVs can be attributed to this integration preference. In addition, long terminal repeats (LTRs) of some γRVs were shown to act as potent promoters by themselves. Here, we investigate the capacity of different γRV LTRs to drive stable expression within a non-preferred epigenomic environment in the context of diverse retroviral vectors. We demonstrate that different γRV LTRs are either rapidly silenced or remain active for long periods of time with a predominantly active proviral population under normal and retargeted integration. As an alternative to the established γRV systems, the feline leukemia virus and koala retrovirus LTRs are able to drive stable, albeit intensity-diverse, transgene expression. Overall, we show that despite the occurrence of rapid silencing events, most γRV LTRs can drive stable expression outside of their preferred chromatin landscape after retrovirus integrations. Full article
(This article belongs to the Section General Virology)
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18 pages, 404 KiB  
Review
Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?
by Coad Thomas Dow, Ellen S. Pierce and Leonardo A. Sechi
Microorganisms 2024, 12(9), 1890; https://doi.org/10.3390/microorganisms12091890 - 13 Sep 2024
Viewed by 1671
Abstract
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of [...] Read more.
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn’s disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association. Full article
(This article belongs to the Section Medical Microbiology)
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16 pages, 7951 KiB  
Communication
Differential Expression of lncRNAs in HIV Patients with TB and HIV-TB with Anti-Retroviral Treatment
by Victoria A. Reid, Enrique I. Ramos, Raja Veerapandian, Areanna Carmona, Shrikanth S. Gadad and Subramanian Dhandayuthapani
Non-Coding RNA 2024, 10(4), 40; https://doi.org/10.3390/ncrna10040040 - 13 Jul 2024
Cited by 1 | Viewed by 1928
Abstract
Tuberculosis (TB) is the leading cause of death among people with HIV-1 infection. To improve the diagnosis and treatment of HIV-TB patients, it is important to understand the mechanisms underlying these conditions. Here, we used an integrated genomics approach to analyze and determine [...] Read more.
Tuberculosis (TB) is the leading cause of death among people with HIV-1 infection. To improve the diagnosis and treatment of HIV-TB patients, it is important to understand the mechanisms underlying these conditions. Here, we used an integrated genomics approach to analyze and determine the lncRNAs that are dysregulated in HIV-TB patients and HIV-TB patients undergoing anti-retroviral therapy (ART) using a dataset available in the public domain. The analyses focused on the portion of the genome transcribed into non-coding transcripts, which historically have been poorly studied and received less focus. This revealed that Mtb infection in HIV prominently up-regulates the expression of long non-coding RNA (lncRNA) genes DAAM2-AS1, COL4A2-AS1, LINC00599, AC008592.1, and CLRN1-AS1 and down-regulates the expression of lncRNAs AC111000.4, AC100803.3, AC016168.2, AC245100.7, and LINC02073. It also revealed that ART down-regulates the expression of some lncRNA genes (COL4A2-AS1, AC079210.1, MFA-AS1, and LINC01993) that are highly up-regulated in HIV-TB patients. Furthermore, the interrogation of the genomic regions that are associated with regulated lncRNAs showed enrichment for biological processes linked to immune pathways in TB-infected conditions. However, intriguingly, TB patients treated with ART showed completely opposite and non-overlapping pathways. Our findings suggest that lncRNAs could be used to identify critical diagnostic, prognostic, and treatment targets for HIV-TB patients. Full article
(This article belongs to the Section Long Non-Coding RNA)
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17 pages, 1696 KiB  
Review
Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity
by Hirokazu Katoh and Tomoyuki Honda
Biomolecules 2023, 13(12), 1706; https://doi.org/10.3390/biom13121706 - 24 Nov 2023
Cited by 6 | Viewed by 2746
Abstract
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR [...] Read more.
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies. Full article
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17 pages, 12079 KiB  
Article
Genotypic and Phenotypic Characterization of Replication-Competent HIV-2 Isolated from Controllers and Progressors
by Cynthia Lungu, Ronald J. Overmars, Esmée Grundeken, Patrick H. M. Boers, Marchina E. van der Ende, Thibault Mesplède and Rob A. Gruters
Viruses 2023, 15(11), 2236; https://doi.org/10.3390/v15112236 - 9 Nov 2023
Viewed by 1445
Abstract
Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors [...] Read more.
Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2. Full article
(This article belongs to the Section Animal Viruses)
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24 pages, 5398 KiB  
Article
The Antiviral Factor SERINC5 Impairs the Expression of Non-Self-DNA
by Yuhang Shi, Sydney Simpson, Shahad K. Ahmed, Yuexuan Chen, Aidin Tavakoli-Tameh, Sanath Kumar Janaka, David T. Evans and Ruth Serra-Moreno
Viruses 2023, 15(9), 1961; https://doi.org/10.3390/v15091961 - 20 Sep 2023
Cited by 3 | Viewed by 2144
Abstract
SERINC5 is a restriction factor that becomes incorporated into nascent retroviral particles, impairing their ability to infect target cells. In turn, retroviruses have evolved countermeasures against SERINC5. For instance, the primate lentiviruses (HIV and SIV) use Nef, Moloney Murine Leukemia Virus (MLV) uses [...] Read more.
SERINC5 is a restriction factor that becomes incorporated into nascent retroviral particles, impairing their ability to infect target cells. In turn, retroviruses have evolved countermeasures against SERINC5. For instance, the primate lentiviruses (HIV and SIV) use Nef, Moloney Murine Leukemia Virus (MLV) uses GlycoGag, and Equine Infectious Anemia Virus (EIAV) uses S2 to remove SERINC5 from the plasma membrane, preventing its incorporation into progeny virions. Recent studies have shown that SERINC5 also restricts other viruses, such as Hepatitis B Virus (HBV) and Classical Swine Fever Virus (CSFV), although through a different mechanism, suggesting that SERINC5 can interfere with multiple stages of the virus life cycle. To investigate whether SERINC5 can also impact other steps of the replication cycle of HIV, the effects of SERINC5 on viral transcripts, proteins, and virus progeny size were studied. Here, we report that SERINC5 causes significant defects in HIV gene expression, which impacts virion production. While the underlying mechanism is still unknown, we found that the restriction occurs at the transcriptional level and similarly affects plasmid and non-integrated proviral DNA (ectopic or non-self-DNA). However, SERINC5 causes no defects in the expression of viral RNA, host genes, or proviral DNA that is integrated in the cellular genome. Hence, our findings reveal that SERINC5’s actions in host defense extend beyond blocking virus entry. Full article
(This article belongs to the Section General Virology)
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23 pages, 6449 KiB  
Article
Specialized DNA Structures Act as Genomic Beacons for Integration by Evolutionarily Diverse Retroviruses
by Hinissan P. Kohio, Hannah O. Ajoge, Macon D. Coleman, Emmanuel Ndashimye, Richard M. Gibson, Eric J. Arts and Stephen D. Barr
Viruses 2023, 15(2), 465; https://doi.org/10.3390/v15020465 - 7 Feb 2023
Cited by 2 | Viewed by 1939
Abstract
Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily [...] Read more.
Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily diverse retroviruses, including new experimental data from HIV-1 subtypes A, B, C and D. We show here that evolutionarily divergent retroviruses exhibit distinct integration site profiles with strong preferences for integration near non-canonical B-form DNA (non-B DNA). We also show that in vivo-derived HIV-1 integration sites are significantly more enriched in transcriptionally silent regions and transcription-silencing non-B DNA features of the genome compared to in vitro-derived HIV-1 integration sites. Integration sites from individuals infected with HIV-1 subtype A, B, C or D viruses exhibited different preferences for common genomic and non-B DNA features. In addition, we identified several integration site hotspots shared between different HIV-1 subtypes, all of which were located in the non-B DNA feature slipped DNA. Together, these data show that although evolutionarily divergent retroviruses exhibit distinct integration site profiles, they all target non-B DNA for integration. These findings provide new insight into how retroviruses integrate into genomes for long-term survival. Full article
(This article belongs to the Special Issue Omics of Virus-Host Interactions)
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28 pages, 2775 KiB  
Review
Multimodal Functionalities of HIV-1 Integrase
by Alan N. Engelman and Mamuka Kvaratskhelia
Viruses 2022, 14(5), 926; https://doi.org/10.3390/v14050926 - 28 Apr 2022
Cited by 13 | Viewed by 3955
Abstract
Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. Co-packaged with viral RNA and reverse transcriptase into capsid-encased viral cores, human immunodeficiency virus 1 (HIV-1) integrase has long been implicated in reverse transcription and virion maturation. However, the underlying [...] Read more.
Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. Co-packaged with viral RNA and reverse transcriptase into capsid-encased viral cores, human immunodeficiency virus 1 (HIV-1) integrase has long been implicated in reverse transcription and virion maturation. However, the underlying mechanisms of integrase in these non-catalytic-related viral replication steps have remained elusive. Recent results have shown that integrase binds genomic RNA in virions, and that mutational or pharmacological disruption of integrase-RNA binding yields eccentric virion particles with ribonucleoprotein complexes situated outside of the capsid shell. Such viruses are defective for reverse transcription due to preferential loss of integrase and viral RNA from infected target cells. Parallel research has revealed defective integrase-RNA binding and eccentric particle formation as common features of class II integrase mutant viruses, a phenotypic grouping of viruses that display defects at steps beyond integration. In light of these new findings, we propose three new subclasses of class II mutant viruses (a, b, and c), all of which are defective for integrase-RNA binding and particle morphogenesis, but differ based on distinct underlying mechanisms exhibited by the associated integrase mutant proteins. We also assess how these findings inform the role of integrase in HIV-1 particle maturation. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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14 pages, 2568 KiB  
Review
Nuclear Import of HIV-1
by Qi Shen, Chunxiang Wu, Christian Freniere, Therese N. Tripler and Yong Xiong
Viruses 2021, 13(11), 2242; https://doi.org/10.3390/v13112242 - 8 Nov 2021
Cited by 22 | Viewed by 4874
Abstract
The delivery of the HIV-1 genome into the nucleus is an indispensable step in retroviral infection of non-dividing cells, but the mechanism of HIV-1 nuclear import has been a longstanding debate due to controversial experimental evidence. It was commonly believed that the HIV-1 [...] Read more.
The delivery of the HIV-1 genome into the nucleus is an indispensable step in retroviral infection of non-dividing cells, but the mechanism of HIV-1 nuclear import has been a longstanding debate due to controversial experimental evidence. It was commonly believed that the HIV-1 capsid would need to disassemble (uncoat) in the cytosol before nuclear import because the capsid is larger than the central channel of nuclear pore complexes (NPCs); however, increasing evidence demonstrates that intact, or nearly intact, HIV-1 capsid passes through the NPC to enter the nucleus. With the protection of the capsid, the HIV-1 core completes reverse transcription in the nucleus and is translocated to the integration site. Uncoating occurs while, or after, the viral genome is released near the integration site. These independent discoveries reveal a compelling new paradigm of this important step of the HIV-1 life cycle. In this review, we summarize the recent studies related to HIV-1 nuclear import, highlighting the spatial–temporal relationship between the nuclear entry of the virus core, reverse transcription, and capsid uncoating. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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14 pages, 1043 KiB  
Review
The Role of Capsid in HIV-1 Nuclear Entry
by Anabel Guedán, Eve R. Caroe, Genevieve C. R. Barr and Kate N. Bishop
Viruses 2021, 13(8), 1425; https://doi.org/10.3390/v13081425 - 22 Jul 2021
Cited by 17 | Viewed by 3829
Abstract
HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following [...] Read more.
HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following membrane fusion, the viral capsid (CA) lattice, which forms the outer face of the retroviral core, makes numerous interactions with cellular proteins that orchestrate the progress of HIV-1 through the replication cycle. The ability of CA to interact with nuclear pore proteins and other host factors around the nuclear pore determines whether nuclear entry occurs. Uncoating, the process by which the CA lattice opens and/or disassembles, is another critical step that must occur prior to integration. Both early and delayed uncoating have detrimental effects on viral infectivity. How uncoating relates to nuclear entry is currently hotly debated. Recent technological advances have led to intense discussions about the timing, location, and requirements for uncoating and have prompted the field to consider alternative uncoating scenarios that presently focus on uncoating at the nuclear pore and within the nuclear compartment. This review describes recent advances in the study of HIV-1 nuclear entry, outlines the interactions of the retroviral CA protein, and discusses the challenges of investigating HIV-1 uncoating. Full article
(This article belongs to the Special Issue Cell-Host Interplay for Viral Nuclear Import)
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13 pages, 4183 KiB  
Communication
Metagenomic Snapshots of Viral Components in Guinean Bats
by Roberto J. Hermida Lorenzo, Dániel Cadar, Fara Raymond Koundouno, Javier Juste, Alexandra Bialonski, Heike Baum, Juan Luis García-Mudarra, Henry Hakamaki, András Bencsik, Emily V. Nelson, Miles W. Carroll, N’Faly Magassouba, Stephan Günther, Jonas Schmidt-Chanasit, César Muñoz Fontela and Beatriz Escudero-Pérez
Microorganisms 2021, 9(3), 599; https://doi.org/10.3390/microorganisms9030599 - 15 Mar 2021
Cited by 10 | Viewed by 4098
Abstract
To prevent the emergence of zoonotic infectious diseases and reduce their epidemic potential, we need to understand their origins in nature. Bats in the order Chiroptera are widely distributed worldwide and are natural reservoirs of prominent zoonotic viruses, including Nipah virus, Marburg virus, [...] Read more.
To prevent the emergence of zoonotic infectious diseases and reduce their epidemic potential, we need to understand their origins in nature. Bats in the order Chiroptera are widely distributed worldwide and are natural reservoirs of prominent zoonotic viruses, including Nipah virus, Marburg virus, and possibly SARS-CoV-2. In this study, we applied unbiased metagenomic and metatranscriptomic approaches to decipher the virosphere of frugivorous and insectivorous bat species captured in Guéckédou, Guinea, the epicenter of the West African Ebola virus disease epidemic in 2013–2016. Our study provides a snapshot of the viral diversity present in these bat species, with several novel viruses reported for the first time in bats, as well as some bat viruses closely related to known human or animal pathogens. In addition, analysis of Mops condylurus genomic DNA samples revealed the presence of an Ebola virus nucleoprotein (NP)-derived pseudogene inserted in its genome. These findings provide insight into the evolutionary traits of several virus families in bats and add evidence that nonretroviral integrated RNA viruses (NIRVs) derived from filoviruses may be common in bat genomes. Full article
(This article belongs to the Special Issue Bats in Infectiology Research—Novel Tools and New Findings)
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14 pages, 3648 KiB  
Review
HIV Capsid and Integration Targeting
by Alan N. Engelman
Viruses 2021, 13(1), 125; https://doi.org/10.3390/v13010125 - 18 Jan 2021
Cited by 32 | Viewed by 5615
Abstract
Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear [...] Read more.
Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear environment where the chromosomes reside. Retroviral integration is non-random, with different types of virus-host interactions impacting where in the host chromatin integration takes place. Lentiviruses such as HIV efficiently infect interphase cells because their RTCs have evolved to usurp cellular nuclear import transport mechanisms, and research over the past decade has revealed specific interactions between the HIV capsid protein and nucleoporin (Nup) proteins such as Nup358 and Nup153. The interaction of HIV capsid with cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular cleavage and polyadenylation complex, helps to dictate nuclear import as well as post-nuclear RTC invasion. In the absence of the capsid-CPSF6 interaction, RTCs are precluded from reaching nuclear speckles and gene-rich regions of chromatin known as speckle-associated domains, and instead mis-target lamina-associated domains out at the nuclear periphery. Highlighting this area of research, small molecules that inhibit capsid-host interactions important for integration site targeting are highly potent antiviral compounds. Full article
(This article belongs to the Special Issue Capsid-Targeting Antivirals and Host Factors)
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21 pages, 3701 KiB  
Article
HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice
by Marina Jerebtsova, Asrar Ahmad, Xiaomei Niu, Ornela Rutagarama and Sergei Nekhai
Viruses 2020, 12(2), 204; https://doi.org/10.3390/v12020204 - 12 Feb 2020
Cited by 6 | Viewed by 3190
Abstract
Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide [...] Read more.
Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide (LPS) induced significantly higher levels of neutrophil infiltration in the lungs compared to wild-type (WT) mice. In WT mice, the initial neutrophil infiltration was followed by macrophage infiltration and fast resolution of leukocytes infiltration. In HIV-Tg mice, resolution of lung infiltration by both neutrophils and macrophages was significantly delayed, with macrophages accumulating in the lumen of lung capillaries resulting in a 45% higher rate of mortality. Trans-endothelial migration of HIV-Tg macrophages was significantly reduced in vitro and this reduction correlated with lower HIV-1 gene expression. HIV-1 transcription inhibitor, 1E7-03, enhanced trans-endothelial migration of HIV-Tg macrophages in vitro, decreased lung neutrophil infiltration in vivo, and increased lung macrophage levels in HIV-Tg mice. Moreover, 1E7-03 reduced levels of inflammatory IL-6 cytokine, improved bleeding score and decreased lung injury. Together this indicates that inhibitors of HIV-1 transcription can correct abnormal dynamics of leukocyte infiltration in HIV-Tg, pointing to the utility of transcription inhibition in the treatment of HIV-1 associated chronic lung disease. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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16 pages, 3959 KiB  
Article
Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression
by Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Keisuke Ae, Seiichi Matsumoto, Subbaya Subramanian and Takuro Nakamura
Cancers 2020, 12(2), 324; https://doi.org/10.3390/cancers12020324 - 30 Jan 2020
Cited by 13 | Viewed by 4416
Abstract
SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells [...] Read more.
SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by SS18-SSX1 introduction into mesenchymal cells and Tle1 and Atf2 upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. miR-199a2 and miR-214 upregulation within the Dnm3 locus was observed. SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis. miR-214 functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., Cxcl15/IL8). Our results emphasize the role of miR-214 in tumor development and disease progression. Full article
(This article belongs to the Collection Carcinogenesis Model)
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24 pages, 4020 KiB  
Review
Host-HIV-1 Interactome: A Quest for Novel Therapeutic Intervention
by Ekta Shukla and Radha Chauhan
Cells 2019, 8(10), 1155; https://doi.org/10.3390/cells8101155 - 27 Sep 2019
Cited by 14 | Viewed by 11437
Abstract
The complex nature and structure of the human immunodeficiency virus has rendered the cure for HIV infections elusive. The advances in antiretroviral treatment regimes and the development of highly advanced anti-retroviral therapy, which primarily targets the HIV enzymes, have dramatically changed the face [...] Read more.
The complex nature and structure of the human immunodeficiency virus has rendered the cure for HIV infections elusive. The advances in antiretroviral treatment regimes and the development of highly advanced anti-retroviral therapy, which primarily targets the HIV enzymes, have dramatically changed the face of the HIV epidemic worldwide. Despite this remarkable progress, patients treated with these drugs often witness inadequate efficacy, compound toxicity and non-HIV complications. Considering the limited inventory of druggable HIV proteins and their susceptibility to develop drug resistance, recent attempts are focussed on targeting HIV-host interactomes that are essential for viral reproduction. Noticeably, unlike other viruses, HIV subverts the host nuclear pore complex to enter into and exit through the nucleus. Emerging evidence suggests a crucial role of interactions between HIV-1 proteins and host nucleoporins that underlie the import of the pre-integration complex into the nucleus and export of viral RNAs into the cytoplasm during viral replication. Nevertheless, the interaction of HIV-1 with nucleoporins has been poorly described and the role of nucleoporins during nucleocytoplasmic transport of HIV-1 still remains unclear. In this review, we highlight the advances and challenges in developing a more effective antiviral arsenal by exploring critical host-HIV interactions with a special focus on nuclear pore complex (NPC) and nucleoporins. Full article
(This article belongs to the Special Issue Nuclear Pore Complex in Nanomedicine)
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