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Viruses
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Molecular Genetics of Retrovirus Replication
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Molecular Genetics of Retrovirus Replication

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 38710

Special Issue Editors

Dr. Judith G. Levin

E-Mail Website
Guest Editor
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA
Interests: HIV and related retroviruses; reverse transcription; genomic RNA-protein interactions; HIV assembly; human APOBEC3 restriction proteins
Dr. Karin Musier-Forsyth

E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, USA
Interests: HIV and related retroviruses; retroviral assembly, genomic RNA packaging and host cell-viral interactions; protein-RNA interactions; aminoacyl-tRNA synthetases
Special Issues, Collections and Topics in MDPI journals
Dr. Alan Rein

E-Mail Website
Guest Editor
HIV Dynamics and Replication Program, National Cancer Institute-Frederick, National Institutes of Health, USA
Interests: molecular mechanisms of retrovirus replication; mechanisms of action of antiretroviral host restriction factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Within a period of little more than ten years, there were two transformative events that changed the retrovirus field and resulted in a major expansion of the retrovirus scientific community. The first event was the discovery of reverse transcriptase in 1970. Soon thereafter, these viruses, formerly termed “RNA Tumor Viruses”, became known as “Retroviruses”. The second event was the emergence of AIDS, initially a mysterious immunodeficiency disease that led to a global pandemic and was shown to result from infection by a novel human retrovirus called HIV. Most importantly, these two events occurred at a time when advanced molecular technologies including molecular cloning were being developed.

In the intervening years, much has been learned. However, despite the availability of  effective anti-HIV drug therapy, according to UNAIDS estimates, in 2019, 1.7 million people became newly infected with HIV and 690,000 died from AIDS-related illnesses. Clearly, there is still an urgent need for new discoveries that could stimulate development of novel antiviral strategies.  

This Special Issue will focus on the “Molecular Genetics of Retrovirus Replication” and highlight current trends in retrovirus research. We invite submission of reviews on relevant subjects such as molecular analysis of events in the virus replication cycle, protein-nucleic acid interactions, structural analysis, and the activity of host factors that influence virus replication. Consideration of future directions of retrovirus research would also be welcome.

Dr. Judith G. Levin
Dr. Karin Musier-Forsyth
Dr. Alan Rein
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • virus entry
  • virus assembly and processing
  • reverse transcription
  • integration
  • virion ultrastructure
  • viral accessory proteins
  • structure and function of Gag proteins
  • genomic RNA structure and function
  • viral Protein-RNA interactions
  • host factors

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Published Papers (10 papers)

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Editorial

Jump to: Review

3 pages, 185 KiB  
Editorial
Molecular Genetics of Retrovirus Replication
by Judith G. Levin, Karin Musier-Forsyth and Alan Rein
Viruses 2023, 15(7), 1549; https://doi.org/10.3390/v15071549 - 14 Jul 2023
Cited by 2 | Viewed by 1446
Abstract
Despite the availability of effective anti-HIV drug therapy, according to UNAIDS estimates, 1 [...] Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)

Review

Jump to: Editorial

31 pages, 3333 KiB  
Review
Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein
by Victoria Hogan and Welkin E. Johnson
Viruses 2023, 15(2), 274; https://doi.org/10.3390/v15020274 - 18 Jan 2023
Cited by 10 | Viewed by 5439
Abstract
After the onset of the AIDS pandemic, HIV-1 (genus Lentivirus) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the Alpharetrovirus, Gammaretrovirus and [...] Read more.
After the onset of the AIDS pandemic, HIV-1 (genus Lentivirus) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the Alpharetrovirus, Gammaretrovirus and Deltaretrovirus genera. For example, oncogenic model system viruses such as Rous sarcoma virus (RSV, Alpharetrovirus), murine leukemia virus (MLV, Gammaretrovirus) and human T-cell leukemia viruses (HTLV-I and HTLV-II, Deltaretrovirus) encode Envs that are structurally and functionally distinct from HIV Env. We refer to these as Gamma-type Envs. Gamma-type Envs are probably the most widespread retroviral Envs in nature. They are found in exogenous and endogenous retroviruses representing a broad spectrum of vertebrate hosts including amphibians, birds, reptiles, mammals and fish. In endogenous form, gamma-type Envs have been evolutionarily coopted numerous times, most notably as placental syncytins (e.g., human SYNC1 and SYNC2). Remarkably, gamma-type Envs are also found outside of the Retroviridae. Gp2 proteins of filoviruses (e.g., Ebolavirus) and snake arenaviruses in the genus Reptarenavirus are gamma-type Env homologs, products of ancient recombination events involving viruses of different Baltimore classes. Distinctive hallmarks of gamma-type Envs include a labile disulfide bond linking the surface and transmembrane subunits, a multi-stage attachment and fusion mechanism, a highly conserved (but poorly understood) “immunosuppressive domain”, and activation by the viral protease during virion maturation. Here, we synthesize work from diverse retrovirus model systems to illustrate these distinctive properties and to highlight avenues for further exploration of gamma-type Env structure and function. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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19 pages, 1741 KiB  
Review
Viral and Host Factors Regulating HIV-1 Envelope Protein Trafficking and Particle Incorporation
by Boris Anokhin and Paul Spearman
Viruses 2022, 14(8), 1729; https://doi.org/10.3390/v14081729 - 5 Aug 2022
Cited by 10 | Viewed by 3578
Abstract
The HIV-1 envelope glycoprotein (Env) is an essential structural component of the virus, serving as the receptor-binding protein and principal neutralizing determinant. Env trimers are incorporated into developing particles at the plasma membrane of infected cells. Incorporation of HIV-1 Env into particles in [...] Read more.
The HIV-1 envelope glycoprotein (Env) is an essential structural component of the virus, serving as the receptor-binding protein and principal neutralizing determinant. Env trimers are incorporated into developing particles at the plasma membrane of infected cells. Incorporation of HIV-1 Env into particles in T cells and macrophages is regulated by the long Env cytoplasmic tail (CT) and the matrix region of Gag. The CT incorporates motifs that interact with cellular factors involved in endosomal trafficking. Env follows an unusual pathway to arrive at the site of particle assembly, first traversing the secretory pathway to the plasma membrane (PM), then undergoing endocytosis, followed by directed sorting to the site of particle assembly on the PM. Many aspects of Env trafficking remain to be defined, including the sequential events that occur following endocytosis, leading to productive recycling and particle incorporation. This review focuses on the host factors and pathways involved in Env trafficking, and discusses leading models of Env incorporation into particles. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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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 3723
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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17 pages, 1407 KiB  
Review
Relationship between HIV-1 Gag Multimerization and Membrane Binding
by Christopher Sumner and Akira Ono
Viruses 2022, 14(3), 622; https://doi.org/10.3390/v14030622 - 16 Mar 2022
Cited by 12 | Viewed by 3358
Abstract
HIV-1 viral particle assembly occurs specifically at the plasma membrane and is driven primarily by the viral polyprotein Gag. Selective association of Gag with the plasma membrane is a key step in the viral assembly pathway, which is traditionally attributed to the MA [...] Read more.
HIV-1 viral particle assembly occurs specifically at the plasma membrane and is driven primarily by the viral polyprotein Gag. Selective association of Gag with the plasma membrane is a key step in the viral assembly pathway, which is traditionally attributed to the MA domain. MA regulates specific plasma membrane binding through two primary mechanisms including: (1) specific interaction of the MA highly basic region (HBR) with the plasma membrane phospholipid phosphatidylinositol (4,5) bisphosphate [PI(4,5)P2], and (2) tRNA binding to the MA HBR, which prevents Gag association with non-PI(4,5)P2 containing membranes. Gag multimerization, driven by both CA–CA inter-protein interactions and NC-RNA binding, also plays an essential role in viral particle assembly, mediating the establishment and growth of the immature Gag lattice on the plasma membrane. In addition to these functions, the multimerization of HIV-1 Gag has also been demonstrated to enhance its membrane binding activity through the MA domain. This review provides an overview of the mechanisms regulating Gag membrane binding through the MA domain and multimerization through the CA and NC domains, and examines how these two functions are intertwined, allowing for multimerization mediated enhancement of Gag membrane binding. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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12 pages, 2281 KiB  
Review
Structural Analysis of Retrovirus Assembly and Maturation
by Anna-Sophia Krebs, Luiza M. Mendonça and Peijun Zhang
Viruses 2022, 14(1), 54; https://doi.org/10.3390/v14010054 - 29 Dec 2021
Cited by 12 | Viewed by 3761
Abstract
Retroviruses have a very complex and tightly controlled life cycle which has been studied intensely for decades. After a virus enters the cell, it reverse-transcribes its genome, which is then integrated into the host genome, and subsequently all structural and regulatory proteins are [...] Read more.
Retroviruses have a very complex and tightly controlled life cycle which has been studied intensely for decades. After a virus enters the cell, it reverse-transcribes its genome, which is then integrated into the host genome, and subsequently all structural and regulatory proteins are transcribed and translated. The proteins, along with the viral genome, assemble into a new virion, which buds off the host cell and matures into a newly infectious virion. If any one of these steps are faulty, the virus cannot produce infectious viral progeny. Recent advances in structural and molecular techniques have made it possible to better understand this class of viruses, including details about how they regulate and coordinate the different steps of the virus life cycle. In this review we summarize the molecular analysis of the assembly and maturation steps of the life cycle by providing an overview on structural and biochemical studies to understand these processes. We also outline the differences between various retrovirus families with regards to these processes. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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18 pages, 2343 KiB  
Review
Inositol Phosphates and Retroviral Assembly: A Cellular Perspective
by Clifton L. Ricaña and Robert A. Dick
Viruses 2021, 13(12), 2516; https://doi.org/10.3390/v13122516 - 15 Dec 2021
Cited by 4 | Viewed by 3993
Abstract
Understanding the molecular mechanisms of retroviral assembly has been a decades-long endeavor. With the recent discovery of inositol hexakisphosphate (IP6) acting as an assembly co-factor for human immunodeficiency virus (HIV), great strides have been made in retroviral research. In this review, the enzymatic [...] Read more.
Understanding the molecular mechanisms of retroviral assembly has been a decades-long endeavor. With the recent discovery of inositol hexakisphosphate (IP6) acting as an assembly co-factor for human immunodeficiency virus (HIV), great strides have been made in retroviral research. In this review, the enzymatic pathways to synthesize and metabolize inositol phosphates (IPs) relevant to retroviral assembly are discussed. The functions of these enzymes and IPs are outlined in the context of the cellular biology important for retroviruses. Lastly, the recent advances in understanding the role of IPs in retroviral biology are surveyed. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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14 pages, 587 KiB  
Review
Silencing of Unintegrated Retroviral DNAs
by Stephen P. Goff
Viruses 2021, 13(11), 2248; https://doi.org/10.3390/v13112248 - 9 Nov 2021
Cited by 9 | Viewed by 3581
Abstract
Retroviral infection delivers an RNA genome into the cytoplasm that serves as the template for the synthesis of a linear double-stranded DNA copy by the viral reverse transcriptase. Within the nucleus this linear DNA gives rise to extrachromosomal circular forms, and in a [...] Read more.
Retroviral infection delivers an RNA genome into the cytoplasm that serves as the template for the synthesis of a linear double-stranded DNA copy by the viral reverse transcriptase. Within the nucleus this linear DNA gives rise to extrachromosomal circular forms, and in a key step of the life cycle is inserted into the host genome to form the integrated provirus. The unintegrated DNA forms, like those of DNAs entering cells by other means, are rapidly loaded with nucleosomes and heavily silenced by epigenetic histone modifications. This review summarizes our present understanding of the silencing machinery for the DNAs of the mouse leukemia viruses and human immunodeficiency virus type 1. We consider the potential impact of the silencing on virus replication, on the sensing of the virus by the innate immune system, and on the formation of latent proviruses. We also speculate on the changeover to high expression from the integrated proviruses in permissive cell types, and briefly consider the silencing of proviruses even after integration in embryonic stem cells and other developmentally primitive cell types. 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 21 | Viewed by 4645
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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16 pages, 703 KiB  
Review
Disassembling the Nature of Capsid: Biochemical, Genetic, and Imaging Approaches to Assess HIV-1 Capsid Functions
by Zachary Ingram, Douglas K. Fischer and Zandrea Ambrose
Viruses 2021, 13(11), 2237; https://doi.org/10.3390/v13112237 - 7 Nov 2021
Cited by 8 | Viewed by 3488
Abstract
The human immunodeficiency virus type 1 (HIV-1) capsid and its disassembly, or capsid uncoating, has remained an active area of study over the past several decades. Our understanding of the HIV-1 capsid as solely a protective shell has since shifted with discoveries linking [...] Read more.
The human immunodeficiency virus type 1 (HIV-1) capsid and its disassembly, or capsid uncoating, has remained an active area of study over the past several decades. Our understanding of the HIV-1 capsid as solely a protective shell has since shifted with discoveries linking it to other complex replication events. The interplay of the HIV-1 capsid with reverse transcription, nuclear import, and integration has led to an expansion of knowledge of capsid functionality. Coincident with advances in microscopy, cell, and biochemistry assays, several models of capsid disassembly have been proposed, in which it occurs in either the cytoplasmic, nuclear envelope, or nuclear regions of the cell. Here, we discuss how the understanding of the HIV-1 capsid has evolved and the key methods that made these discoveries possible. Full article
(This article belongs to the Special Issue Molecular Genetics of Retrovirus Replication)
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