scholarly journals Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2221
Author(s):  
Roger H. Miller ◽  
Alexis Zimmer ◽  
Gilles Moutot ◽  
Jean-Michel Mesnard ◽  
Nathalie Chazal
Keyword(s):  
Virus Type ◽  
Leukemia Virus ◽  
Genome Replication ◽  
Paradigm Shifts ◽  
Antisense Transcripts ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
History Of ◽  
Hiv 1

Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.

scholarly journals Analysis of the Interaction of Primate Retroviruses with the Human RNA Interference Machinery

2007 ◽  
Vol 81 (22) ◽  
pp. 12218-12226 ◽  
Author(s):  
Jennifer Lin ◽  
Bryan R. Cullen
Keyword(s):  
Rna Interference ◽  
Virus Type ◽  
Leukemia Virus ◽  
Foamy Virus ◽  
Human Cells ◽  
Small Interfering Rnas ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
Hiv 1

ABSTRACT The question of whether retroviruses, including human immunodeficiency virus type 1 (HIV-1), interact with the cellular RNA interference machinery has been controversial. Here, we present data showing that neither HIV-1 nor human T-cell leukemia virus type 1 (HTLV-1) expresses significant levels of either small interfering RNAs or microRNAs in persistently infected T cells. We also demonstrate that the retroviral nuclear transcription factors HIV-1 Tat and HTLV-1 Tax, as well as the Tas transactivator encoded by primate foamy virus, fail to inhibit RNA interference in human cells. Moreover, the stable expression of physiological levels of HIV-1 Tat did not globally inhibit microRNA production or expression in infected human cells. Together, these data argue that HIV-1 and HTLV-1 neither induce the production of viral small interfering RNAs or microRNAs nor repress the cellular RNA interference machinery in infected cells.

Serological survey of HIV-1, HIV-2 and human T-cell leukemia virus type 1 for suspected AIDS cases in Ghana

AIDS ◽  
1994 ◽  
Vol 8 (9) ◽  
pp. 1257-1261 ◽  
Author(s):  
Osamu Hishida ◽  
Nana K. Ayisi ◽  
Michael Aidoo ◽  
James Brandful ◽  
William Ampofo ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Serological Survey ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

scholarly journals Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases

2005 ◽  
Vol 86 (9) ◽  
pp. 2489-2494 ◽  
Author(s):  
Renaud Mahieux ◽  
Rodolphe Suspène ◽  
Frédéric Delebecque ◽  
Michel Henry ◽  
Olivier Schwartz ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Cytidine Deaminases ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

In the absence of the human immunodeficiency virus type 1 (HIV-1) Vif protein, the host-cell cytidine deaminases APOBEC3F and -3G are co-packaged along with virion RNA. Upon infection of target cells, nascent single-stranded DNA can be edited extensively, invariably giving rise to defective genomes called G→A hypermutants. Although human T-cell leukemia virus type 1 (HTLV-1) replicates in the same cell type as HIV-1, it was shown here that HTLV-1 is relatively resistant to the antiviral effects mediated by human APOBEC3B, -3C, -3F and -3G. Nonetheless, a small percentage of genomes (0·1<f<5 %) were edited extensively: up to 97 % of cytidine targets were deaminated. In contrast, hypermutated HTLV-1 genomes were not identified in peripheral blood mononuclear cell DNA from ten patients with non-malignant HTLV-1 infection. Thus, although HTLV-1 DNA can indeed be edited by at least four APOBEC3 cytidine deaminases in vitro, they are conspicuously absent in vivo.

scholarly journals Inhibitors of Strand Transfer That Prevent Integration and Inhibit Human T-Cell Leukemia Virus Type 1 Early Replication

2008 ◽  
Vol 52 (10) ◽  
pp. 3532-3541 ◽  
Author(s):  
Samira Rabaaoui ◽  
Fatima Zouhiri ◽  
Agnès Lançon ◽  
Hervé Leh ◽  
Jean d'Angelo ◽  
...  
Keyword(s):  
Virus Type ◽  
Ex Vivo ◽  
Leukemia Virus ◽  
Strand Transfer ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

ABSTRACT The replication of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for the prevention and treatment of HTLV-1-associated diseases.

scholarly journals A Human T-Cell Leukemia Virus Type 1 Regulatory Element Enhances the Immunogenicity of Human Immunodeficiency Virus Type 1 DNA Vaccines in Mice and Nonhuman Primates

2005 ◽  
Vol 79 (14) ◽  
pp. 8828-8834 ◽  
Author(s):  
Dan H. Barouch ◽  
Zhi-yong Yang ◽  
Wing-pui Kong ◽  
Birgit Korioth-Schmitz ◽  
Shawn M. Sumida ◽  
...  
Keyword(s):  
Immune Responses ◽  
Virus Type ◽  
Dna Vaccines ◽  
Leukemia Virus ◽  
Regulatory Elements ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

ABSTRACT Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. Here we investigate a novel approach that optimizes regulatory elements in the plasmid backbone to improve the immunogenicity of DNA vaccines. Among various regions analyzed, we found that the addition of a regulatory sequence from the R region of the long terminal repeat from human T-cell leukemia virus type 1 (HTLV-1) to the cytomegalovirus (CMV) enhancer/promoter increased transgene expression 5- to 10-fold and improved cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens. In cynomolgus monkeys, DNA vaccines containing the CMV enhancer/promoter with the HTLV-1 R region (CMV/R) induced markedly higher cellular immune responses to HIV-1 Env from clades A, B, and C and to HIV-1 Gag-Pol-Nef compared with the parental DNA vaccines. These data demonstrate that optimization of specific regulatory elements can substantially improve the immunogenicity of DNA vaccines encoding multiple antigens in small animals and in nonhuman primates. This strategy could therefore be explored as a potential method to enhance DNA vaccine immunogenicity in humans.

scholarly journals Interactions of Murine APOBEC3 and Human APOBEC3G with Murine Leukemia Viruses

2008 ◽  
Vol 82 (13) ◽  
pp. 6566-6575 ◽  
Author(s):  
Samuel J. Rulli ◽  
Jane Mirro ◽  
Shawn A. Hill ◽  
Patricia Lloyd ◽  
Robert J. Gorelick ◽  
...  
Keyword(s):  
Virus Type ◽  
Leukemia Virus ◽  
Viral Dna ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
Apobec3 Proteins ◽  
Hiv 1 ◽  
Murine Leukemia ◽  
Human Apobec3g

ABSTRACT APOBEC3 proteins are cytidine deaminases which help defend cells against retroviral infections. One antiviral mechanism involves deaminating dC residues in minus-strand DNA during reverse transcription, resulting in G-to-A mutations in the coding strand. We investigated the effects of mouse APOBEC3 (mA3) and human APOBEC3G (hA3G) upon Moloney murine leukemia virus (MLV). We find that mA3 inactivates MLV but is significantly less effective against MLV than is hA3G. In contrast, mA3 is as potent against human immunodeficiency virus type 1 (HIV-1, lacking the protective Vif protein) as is hA3G. The two APOBEC3 proteins are packaged to similar extents in MLV particles. Dose-response profiles imply that a single APOBEC3 molecule (or oligomer) is sufficient to inactivate an MLV particle. The inactivation of MLV by mA3 and hA3G is accompanied by relatively small reductions in the amount of viral DNA in infected cells. Although hA3G induces significant levels of G-to-A mutations in both MLV and HIV DNAs, and mA3 induces these mutations in HIV DNA, no such mutations were detected in DNA synthesized by MLV inactivated by mA3. Thus, MLV has apparently evolved to partially resist the antiviral effects of mA3 and to totally resist the ability of mA3 to induce G-to-A mutation in viral DNA. Unlike the resistance of HIV-1 and human T-cell leukemia virus type 1 to hA3G, the resistance of MLV to mA3 is not mediated by the exclusion of APOBEC from the virus particle. The nature of its resistance and the mechanism of inactivation of MLV by mA3 are completely unknown.

scholarly journals Distinct Pathway of Human T-Cell Leukemia Virus Type 1 Gag Punctum Biogenesis Provides New Insights into Enveloped Virus Assembly

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
John P. Eichorst ◽  
Yan Chen ◽  
Joachim D. Mueller ◽  
Louis M. Mansky
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

ABSTRACT The assembly of virus particles is a crucial aspect of virus spread. For retroviruses, the Gag polyprotein is the key driver for virus particle assembly. In order to produce progeny virus, once Gag is translated, it must translocate from the location in the cytoplasm where it is synthesized to the plasma membrane and form an oligomeric lattice that results in Gag puncta. The biogenesis of mature Gag puncta can trigger the budding process, resulting in virus particle production. While some aspects of the dynamics of Gag oligomerization and particle biogenesis have been observed with human immunodeficiency virus type 1 (HIV-1), the process of Gag punctum biogenesis remains poorly understood, particularly for other retroviruses. Here, we have conducted the most detailed studies thus far on Gag punctum biogenesis for human T-cell leukemia virus type 1 (HTLV-1). Using mEos2 photoconvertible fluorescent proteins and total internal reflection fluorescence microscopy (TIRF), we have found that HTLV-1 Gag was recruited to Gag puncta primarily from the plasma membrane. This was in stark contrast to HIV-1 Gag, which was recruited from the cytoplasm. These observations imply fundamental differences among retroviruses regarding the orchestration of Gag punctum biogenesis, which has important general implications for enveloped virus particle assembly. IMPORTANCE This report describes the results of experiments examining the pathway by which the human retroviral Gag protein is recruited to sites along the inner leaflet of the plasma membrane where Gag punctum biogenesis occurs. In particular, clever and sensitive experimental methods were devised to image in living cells fluorescently labeled Gag protein derivatives from human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) at the plasma membrane. The photoconvertible fluorescent protein mEos2 was strategically utilized, as the fluorescence emission of Gag at the plasma membrane could be differentiated from that of cytosolic Gag. This experimental strategy allowed for the determination of the Gag recruitment pathway into Gag puncta. For HTLV-1 Gag, puncta recruited Gag primarily from the plasma membrane, while HIV-1 Gag was recruited from the cytoplasm. These observations represent the first report of HTLV-1 particle biogenesis and its contrast to that of HIV-1. The observed differences in the Gag recruitment pathways used by HTLV-1 and HIV-1 Gag provide key information that is useful for informing the discovery of novel targets for antiretroviral therapies directed at eliminating virus infectivity and spread.

scholarly journals Integrase Inhibitors Effective against Human T-Cell Leukemia Virus Type 1

2011 ◽  
Vol 55 (5) ◽  
pp. 2011-2017 ◽  
Author(s):  
Muhammad Esa Seegulam ◽  
Lee Ratner
Keyword(s):  
Virus Type ◽  
Leukemia Virus ◽  
Cell Leukemia ◽  
Integrase Inhibitors ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Hiv 1

ABSTRACTDrugs targeting the viral enzyme integrase have been in use for several years as part of the treatment regimen for patients with human immunodeficiency virus type 1 (HIV-1), and similar classes of compounds have been shown to inhibit human T-cell leukemia virus type 1 (HTLV-1) integrationin vitro. The current study shows that the clinically approved HIV-1 integrase inhibitor, raltegravir, as well as the more recent diketo acid derivative, MK-2048, are active inhibitors of HTLV-1 infectionin vitro. These agents were effective in inhibiting cell-free and cell-to-cell transmission of HTLV-1 in lymphoid and nonlymphoid cells. The drugs also inhibited HTLV-1 immortalization of human peripheral blood mononuclear cells. A novel adaptation of theAluassay for viral integration was used to show that the drugs inhibit viral integration without affecting reverse transcription. These data support the administration of raltegravir and other integrase inhibitors as treatments for patients with HTLV-1-associated diseases.

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