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4 pages, 152 KiB

Open AccessEditorial

Special Issue: Retroviral Enzymes

by Luis Menéndez-Arias

Viruses 2010, 2(5), 1181-1184; https://doi.org/10.3390/v2051181 - 7 May 2010

Cited by 4 | Viewed by 8347

Abstract

The retroviral RNA genome encodes for three enzymes essential for virus replication: (i) the viral protease (PR), that converts the immature virion into a mature virus through the cleavage of precursor polypeptides; (ii) the reverse transcriptase (RT), responsible for the conversion of the [...] Read more.

The retroviral RNA genome encodes for three enzymes essential for virus replication: (i) the viral protease (PR), that converts the immature virion into a mature virus through the cleavage of precursor polypeptides; (ii) the reverse transcriptase (RT), responsible for the conversion of the single-stranded genomic RNA into double-stranded proviral DNA; and (iii) the integrase (IN) that inserts the proviral DNA into the host cell genome. All of them are important targets for therapeutic intervention. This Special Issue provides authoritative reviews on the most recent research towards a better understanding of structure-function relationships in retroviral enzymes. The Issue includes three reviews on retroviral PRs, seven on RT and reverse transcription, and four dedicated to viral integration. [...] Full article

(This article belongs to the Special Issue Retroviral Enzymes)

Review

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36 pages, 254 KiB

Open AccessReview

Interactions of Host Proteins with the Murine Leukemia Virus Integrase

by Barbara Studamire and Stephen P. Goff

Viruses 2010, 2(5), 1110-1145; https://doi.org/10.3390/v2051110 - 5 May 2010

Cited by 11 | Viewed by 11479

Abstract

Retroviral infections cause a variety of cancers in animals and a number of diverse diseases in humans such as leukemia and acquired immune deficiency syndrome. Productive and efficient proviral integration is critical for retroviral function and is the key step in establishing a [...] Read more.

Retroviral infections cause a variety of cancers in animals and a number of diverse diseases in humans such as leukemia and acquired immune deficiency syndrome. Productive and efficient proviral integration is critical for retroviral function and is the key step in establishing a stable and productive infection, as well as the mechanism by which host genes are activated in leukemogenesis. Host factors are widely anticipated to be involved in all stages of the retroviral life cycle, and the identification of integrase interacting factors has the potential to increase our understanding of mechanisms by which the incoming virus might appropriate cellular proteins to target and capture host DNA sequences. Identification of MoMLV integrase interacting host factors may be key to designing efficient and benign retroviral-based gene therapy vectors; key to understanding the basic mechanism of integration; and key in designing efficient integrase inhibitors. In this review, we discuss current progress in the field of MoMLV integrase interacting proteins and possible roles for these proteins in integration. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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22 pages, 414 KiB

Open AccessReview

Implications of the Nucleocapsid and the Microenvironment in Retroviral Reverse Transcription

by Marylène Mougel, Andrea Cimarelli and Jean-Luc Darlix

Viruses 2010, 2(4), 939-960; https://doi.org/10.3390/v2040939 - 2 Apr 2010

Cited by 14 | Viewed by 13424

Abstract

This mini-review summarizes the process of reverse-transcription, an obligatory step in retrovirus replication during which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded genomic RNA to generate the double-stranded viral DNA while degrading the genomic RNA via its associated RNase H activity. [...] Read more.

This mini-review summarizes the process of reverse-transcription, an obligatory step in retrovirus replication during which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded genomic RNA to generate the double-stranded viral DNA while degrading the genomic RNA via its associated RNase H activity. The hybridization of complementary viral sequences by the nucleocapsid protein (NC) receives a special focus, since it acts to chaperone the strand transfers obligatory for synthesis of the complete viral DNA and flanking long terminal repeats (LTR). Since the physiological microenvironment can impact on reverse-transcription, this mini-review also focuses on factors present in the intra-cellular or extra-cellular milieu that can drastically influence both the timing and the activity of reverse-transcription and hence virus infectivity. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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27 pages, 814 KiB

Open AccessReview

HIV-1 Ribonuclease H: Structure, Catalytic Mechanism and Inhibitors

by Greg L. Beilhartz and Matthias Götte

Viruses 2010, 2(4), 900-926; https://doi.org/10.3390/v2040900 - 30 Mar 2010

Cited by 69 | Viewed by 16662

Abstract

Since the human immunodeficiency virus (HIV) was discovered as the etiological agent of acquired immunodeficiency syndrome (AIDS), it has encouraged much research into antiviral compounds. The reverse transcriptase (RT) of HIV has been a main target for antiviral drugs. However, all drugs developed [...] Read more.

Since the human immunodeficiency virus (HIV) was discovered as the etiological agent of acquired immunodeficiency syndrome (AIDS), it has encouraged much research into antiviral compounds. The reverse transcriptase (RT) of HIV has been a main target for antiviral drugs. However, all drugs developed so far inhibit the polymerase function of the enzyme, while none of the approved antiviral agents inhibit specifically the necessary ribonuclease H (RNase H) function of RT. This review provides a background on structure-function relationships of HIV-1 RNase H, as well as an outline of current attempts to develop novel, potent chemotherapeutics against a difficult drug target. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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33 pages, 2554 KiB

Open AccessReview

Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase

by Kamalendra Singh, Bruno Marchand, Karen A. Kirby, Eleftherios Michailidis and Stefan G. Sarafianos

Viruses 2010, 2(2), 606-638; https://doi.org/10.3390/v2020606 - 11 Feb 2010

Cited by 73 | Viewed by 20574

Abstract

HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of [...] Read more.

HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of wild-type or drug-resistant mutant HIV RTs in the unliganded form or in complex with substrates and/or drugs have offered valuable glimpses into the enzyme’s folding and its interactions with DNA and dNTP substrates, as well as with nucleos(t)ide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTIs) drugs. These studies have been used to interpret a large body of biochemical results and have paved the way for innovative biochemical experiments designed to elucidate the mechanisms of catalysis and drug inhibition of polymerase and RNase H functions of RT. In turn, the combined use of structural biology and biochemical approaches has led to the discovery of novel mechanisms of drug resistance and has contributed to the design of new drugs with improved potency and ability to suppress multi-drug resistant strains. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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31 pages, 623 KiB

Open AccessReview

Initiation of HIV Reverse Transcription

by Catherine Isel, Chantal Ehresmann and Roland Marquet

Viruses 2010, 2(1), 213-243; https://doi.org/10.3390/v2010213 - 18 Jan 2010

Cited by 40 | Viewed by 16341

Abstract

Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an [...] Read more.

Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an RNA/protein complex with very specific structural and functional features, some of which being, in the case of HIV-1, linked to particular isolates. Recent understanding of the tight spatio-temporal regulation of reverse transcription and its importance for viral infectivity further points toward reverse transcription and potentially its initiation step as an important drug target. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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19 pages, 1020 KiB

Open AccessReview

Comparative Studies on Retroviral Proteases: Substrate Specificity

by József Tözsér

Viruses 2010, 2(1), 147-165; https://doi.org/10.3390/v2010147 - 14 Jan 2010

Cited by 37 | Viewed by 15280

Abstract

Exogenous retroviruses are subclassified into seven genera and include viruses that cause diseases in humans. The viral Gag and Gag-Pro-Pol polyproteins are processed by the retroviral protease in the last stage of replication and inhibitors of the HIV-1 protease are widely used in [...] Read more.

Exogenous retroviruses are subclassified into seven genera and include viruses that cause diseases in humans. The viral Gag and Gag-Pro-Pol polyproteins are processed by the retroviral protease in the last stage of replication and inhibitors of the HIV-1 protease are widely used in AIDS therapy. Resistant mutations occur in response to the drug therapy introducing residues that are frequently found in the equivalent position of other retroviral proteases. Therefore, besides helping to understand the general and specific features of these enzymes, comparative studies of retroviral proteases may help to understand the mutational capacity of the HIV-1 protease. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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20 pages, 194 KiB

Open AccessReview

Retroviral Integration Site Selection

by Sébastien Desfarges and Angela Ciuffi

Viruses 2010, 2(1), 111-130; https://doi.org/10.3390/v2010111 - 12 Jan 2010

Cited by 57 | Viewed by 18414

Abstract

The stable insertion of a copy of their genome into the host cell genome is an essential step of the life cycle of retroviruses. The site of viral DNA integration, mediated by the viral-encoded integrase enzyme, has important consequences for both the virus [...] Read more.

The stable insertion of a copy of their genome into the host cell genome is an essential step of the life cycle of retroviruses. The site of viral DNA integration, mediated by the viral-encoded integrase enzyme, has important consequences for both the virus and the host cell. The analysis of retroviral integration site distribution was facilitated by the availability of the human genome sequence, revealing the non-random feature of integration site selection and identifying different favored and disfavored genomic locations for individual retroviruses. This review will summarize the current knowledge about retroviral differences in their integration site preferences as well as the mechanisms involved in this process. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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31 pages, 1044 KiB

Open AccessReview

Current and Novel Inhibitors of HIV Protease

by Jana Pokorná, Ladislav Machala, Pavlína Řezáčová and Jan Konvalinka

Viruses 2009, 1(3), 1209-1239; https://doi.org/10.3390/v1031209 - 11 Dec 2009

Cited by 100 | Viewed by 23860

Abstract

The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in [...] Read more.

The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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29 pages, 665 KiB

Open AccessReview

Mutation Rates and Intrinsic Fidelity of Retroviral Reverse Transcriptases

by Luis Menéndez-Arias

Viruses 2009, 1(3), 1137-1165; https://doi.org/10.3390/v1031137 - 4 Dec 2009

Cited by 92 | Viewed by 18516

Abstract

Retroviruses are RNA viruses that replicate through a DNA intermediate, in a process catalyzed by the viral reverse transcriptase (RT). Although cellular polymerases and host factors contribute to retroviral mutagenesis, the RT errors play a major role in retroviral mutation. RT mutations that [...] Read more.

Retroviruses are RNA viruses that replicate through a DNA intermediate, in a process catalyzed by the viral reverse transcriptase (RT). Although cellular polymerases and host factors contribute to retroviral mutagenesis, the RT errors play a major role in retroviral mutation. RT mutations that affect the accuracy of the viral polymerase have been identified by in vitro analysis of the fidelity of DNA synthesis, by using enzymological (gel-based) and genetic assays (e.g., M13mp2 lacZ forward mutation assays). For several amino acid substitutions, these observations have been confirmed in cell culture using viral vectors. This review provides an update on studies leading to the identification of the major components of the fidelity center in retroviral RTs. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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27 pages, 1295 KiB

Open AccessReview

HIV-1 Protease: Structural Perspectives on Drug Resistance

by Irene T. Weber and Johnson Agniswamy

Viruses 2009, 1(3), 1110-1136; https://doi.org/10.3390/v1031110 - 3 Dec 2009

Cited by 124 | Viewed by 12799

Abstract

Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of [...] Read more.

Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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22 pages, 593 KiB

Open AccessReview

Reverse Transcriptase and Cellular Factors: Regulators of HIV-1 Reverse Transcription

by Kylie Warren, David Warrilow, Luke Meredith and David Harrich

Viruses 2009, 1(3), 873-894; https://doi.org/10.3390/v1030873 - 10 Nov 2009

Cited by 38 | Viewed by 17415

Abstract

There is ample evidence that synthesis of HIV-1 proviral DNA from the viral RNA genome during reverse transcription requires host factors. However, only a few cellular proteins have been described in detail that affect reverse transcription and interact with reverse transcriptase (RT). HIV-1 [...] Read more.

There is ample evidence that synthesis of HIV-1 proviral DNA from the viral RNA genome during reverse transcription requires host factors. However, only a few cellular proteins have been described in detail that affect reverse transcription and interact with reverse transcriptase (RT). HIV-1 integrase is an RT binding protein and a number of IN-binding proteins including INI1, components of the Sin3a complex, and Gemin2 affect reverse transcription. In addition, recent studies implicate the cellular proteins HuR, AKAP149, and DNA topoisomerase I in reverse transcription through an interaction with RT. In this review we will consider interactions of reverse transcription complex with viral and cellular factors and how they affect the reverse transcription process. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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22 pages, 453 KiB

Open AccessReview

The Interaction Between Lentiviral Integrase and LEDGF: Structural and Functional Insights

by Stephen Hare and Peter Cherepanov

Viruses 2009, 1(3), 780-801; https://doi.org/10.3390/v1030780 - 6 Nov 2009

Cited by 20 | Viewed by 16635

Abstract

Since its initial description as an HIV-1 integrase (IN) interactor seven years ago, LEDGF has become one of the best-characterized host factors involved in viral replication. Results of intensive studies in several laboratories indicated that the protein serves as a targeting factor for [...] Read more.

Since its initial description as an HIV-1 integrase (IN) interactor seven years ago, LEDGF has become one of the best-characterized host factors involved in viral replication. Results of intensive studies in several laboratories indicated that the protein serves as a targeting factor for the lentiviral DNA integration machinery, and accounts for the characteristic preference of Lentivirus to integrate within active transcription units. The IN-LEDGF interaction has been put forward as a promising target for antiretroviral drug development and as a potential tool to improve safety of lentiviral vectors for use in gene therapy. Additionally, as a natural ligand of lentiviral IN proteins, LEDGF has been successfully used in structural biology studies of retroviral DNA integration. This review focuses on the structural aspects of the IN-LEDGF interaction and their functional consequences. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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24 pages, 336 KiB

Open AccessReview

HIV-1 Integrase-DNA Recognition Mechanisms

by Jacques J. Kessl, Christopher J. McKee, Jocelyn O. Eidahl, Nikolozi Shkriabai, Ari Katz and Mamuka Kvaratskhelia

Viruses 2009, 1(3), 713-736; https://doi.org/10.3390/v1030713 - 5 Nov 2009

Cited by 13 | Viewed by 15115

Abstract

Integration of a reverse transcribed DNA copy of the HIV viral genome into the host chromosome is essential for virus replication. This process is catalyzed by the virally encoded protein integrase. The catalytic activities, which involve DNA cutting and joining steps, have been [...] Read more.

Integration of a reverse transcribed DNA copy of the HIV viral genome into the host chromosome is essential for virus replication. This process is catalyzed by the virally encoded protein integrase. The catalytic activities, which involve DNA cutting and joining steps, have been recapitulated in vitro using recombinant integrase and synthetic DNA substrates. Biochemical and biophysical studies of these model reactions have been pivotal in advancing our understanding of mechanistic details for how IN interacts with viral and target DNAs, and are the focus of the present review. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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21 pages, 791 KiB

Open AccessReview

Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons: Dynamics of Enzyme: Substrate Interactions

by Daniele Fabris, John P. Marino and Stuart F. J. Le Grice

Viruses 2009, 1(3), 657-677; https://doi.org/10.3390/v1030657 - 4 Nov 2009

Cited by 3 | Viewed by 13790

Abstract

Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3’ terminus must be accommodated by ribonuclease H (RNase H) [...] Read more.

Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3’ terminus must be accommodated by ribonuclease H (RNase H) and DNA polymerase catalytic centers situated at either terminus of the cognate reverse transcriptase (RT), and in the case of the HIV-1 enzyme, ~70Å apart. Communication between RT and the RNA/DNA hybrid therefore appears necessary to promote these events. The crystal structure of the HIV-1 RT/PPT complex, while informative, positions the RNase H active site several bases pairs from the PPT/U3 junction, and thus provides limited information on cleavage specificity. To fill the gap between biochemical and crystallographic approaches, we review a multidisciplinary approach combining chemical probing, mass spectrometry, NMR spectroscopy and single molecule spectroscopy. Our studies also indicate that nonnucleoside RT inhibitors affect enzyme orientation, suggesting initiation of plus-strand DNA synthesis as a potential therapeutic target. Full article

(This article belongs to the Special Issue Retroviral Enzymes)

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