Remarkable Lethal G-to-A Mutations in
            <i>vif-</i>
            Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice

Sato, Kei; Izumi, Tatsuro; Misawa, Naoko; Kobayashi, Tomoko; Yamashita, Yoshiki; Ohmichi, Masahide; Ito, Mamoru; Takaori‐Kondo, Akifumi; Koyanagi, Yoshio

doi:10.1128/jvi.00823-10

Cited by 78 publications

(142 citation statements)

References 62 publications

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“…In this system, human leukocytes including human CD4 ϩ T cells are differentiated de novo and are stably and longitudinally maintained. By using these humanized mice, we have established novel animal models for HIV-1 and Epstein-Barr virus infections and related diseases (44,52,54,55). Particularly noteworthy is that our humanized mice, named NOG-hCD34 mice, are able to recapitulate the characteristics of HIV-1 pathogenesis, such as the depletion of CD4 ϩ T cells in peripheral blood (PB) and the preferential infection of effector memory CD4 ϩ T cells (44,53).…”

Section: Wt]) Hiv-1-infected/transfected Cells In Certain Cd4mentioning

confidence: 99%

“…In order to elucidate the dynamics of human-specific pathogens such as HIV-1 in vivo, we have constructed a humanized mouse model by xenotransplanting human CD34 ϩ hematopoietic stem cells into an immunodeficient NOD/SCID Il2rg Ϫ/Ϫ (NOG) mouse (44,52,55). In this system, human leukocytes including human CD4 ϩ T cells are differentiated de novo and are stably and longitudinally maintained.…”

Section: Wt]) Hiv-1-infected/transfected Cells In Certain Cd4mentioning

confidence: 99%

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Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

Sato

Misawa

Fukuhara

et al. 2012

J Virol

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122

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While human cells express potent antiviral proteins as part of the host defense repertoire, viruses have evolved their own arsenal of proteins to antagonize them. BST2 was identified as an inhibitory cellular protein of HIV-1 replication, which tethers virions to the cell surface to prevent their release. On the other hand, the HIV-1 accessory protein, Vpu, has the ability to downregulate and counteract BST2. Vpu also possesses the ability to downmodulate cellular CD4 and SLAMF6 molecules expressed on infected cells. However, the role of Vpu in HIV-1 infection in vivo remains unclear. Here, using a human hematopoietic stem celltransplanted humanized mouse model, we demonstrate that Vpu contributes to the efficient spread of HIV-1 in vivo during the acute phase of infection. Although Vpu did not affect viral cytopathicity, target cell preference, and the level of viral protein expression, the amount of cell-free virions in vpu-deficient HIV-1-infected mice was profoundly lower than that in wild-type HIV-1-infected mice. We provide a novel insight suggesting that Vpu concomitantly downregulates BST2 and CD4, but not SLAMF6, from the surface of infected cells. Furthermore, we show evidence suggesting that BST2 and CD4 impair the production of cellfree infectious virions but do not associate with the efficiency of cell-to-cell HIV-1 transmission. Taken together, our findings suggest that Vpu downmodulates BST2 and CD4 in infected cells and augments the initial burst of HIV-1 replication in vivo. This is the first report demonstrating the role of Vpu in HIV-1 infection in an in vivo model.

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Section: Wt]) Hiv-1-infected/transfected Cells In Certain Cd4mentioning

confidence: 99%

Section: Wt]) Hiv-1-infected/transfected Cells In Certain Cd4mentioning

confidence: 99%

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

Sato

Misawa

Fukuhara

et al. 2012

J Virol

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122

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“…Further detailed studies revealed that APOBEC molecules are packaged into HIV-1 virions in virus producer cells via a specific interaction with Gag and viral RNA and then exert their deaminase activity in subsequent target cells on a single-stranded DNA (ssDNA) intermediate synthesized by reverse transcriptase (3, 28, 55). Editing can lead to nonsynonymous mutations, such as premature stop codons, in critical proteins (e.g., reverse transcriptase) necessary for virus replication and infectivity, severely impairing the next round of infection (54,64). Extensive studies to assess the antiviral nature of these APOBEC enzymes have been performed across a broad range of retroviruses and hepatitis B virus (HBV) (7,35,36,42,43,50,56,58).…”

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confidence: 99%

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Gee

Ando

Kitayama

et al. 2011

J Virol

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APOBEC1 (A1) is a cytidine deaminase involved in the regulation of lipids in the small intestine. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that is capable of infecting neurons in the brain, causing encephalitis. Here, we show that A1 is induced during encephalitis in neurons of rats infected with HSV-1. In cells stably expressing A1, HSV-1 infection resulted in significantly reduced virus replication compared to that in control cells. Infectivity could be restored to levels comparable to those observed for control cells if A1 expression was silenced by specific A1 short hairpin RNAs (shRNA). Moreover, cytidine deaminase activity appeared to be essential for this inhibition and led to an impaired accumulation of viral mRNA transcripts and DNA copy numbers. The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.The human apolipoprotein B-editing catalytic polypeptide (ABOBEC) family is a group of zinc-dependent DNA and RNA cytidine deaminases and consists of AID, APOBEC1 (A1), APOBEC2 (A2), seven APOBEC3s (APOBEC3A [A3A] to A3H), and APOBEC4 (A4). A1, the first APOBEC to be discovered, is known to introduce a premature stop codon into host apolipoprotein B mRNA in the gastrointestinal tract, an event critical for lipid metabolism (17,40,61). The editing by A1 is highly precise and specifically converts C to U at position 6666 of the apolipoprotein B mRNA substrate (46). Along with APOBEC1 complementation factor (ACF), these two proteins constitute the minimal required components necessary for the editing of apolipoprotein B mRNA in vitro (37).Cytidine deaminases first came into the limelight as antiviral factors after A3G was identified as a cellular restriction factor capable of inhibiting HIV-1 dissemination in the absence of HIV-1 virus infectivity factor (Vif) (56). This molecule was later shown to inhibit retrovirus infection by inducing a massive hypermutation of the murine leukemia virus (MLV) genome (23). Further detailed studies revealed that APOBEC molecules are packaged into HIV-1 virions in virus producer cells via a specific interaction with Gag and viral RNA and then exert their deaminase activity in subsequent target cells on a single-stranded DNA (ssDNA) intermediate synthesized by reverse transcriptase (3, 28, 55). Editing can lead to nonsynonymous mutations, such as premature stop codons, in critical proteins (e.g., reverse transcriptase) necessary for virus replication and infectivity, severely impairing the next round of infection (54,64). Extensive studies to assess the antiviral nature of these APOBEC enzymes have been performed across a broad range of retroviruses and hepatitis B virus (HBV) (7,35,36,42,43,50,56,58).Herpes simplex virus (HSV) is an enveloped, double-stranded DNA (dsDNA) virus and a member of the genus Alphaherpe...

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“…These mouse models were expected to recapitulate various human diseases, including cancer (6-9), infectious disease (10)(11)(12)(13)(14), and graft-versus-host-disease (GVHD) (15,16), and to enhance basic research in human physiology and pathology, as well as the development of clinical drugs. Recently, severely immunodeficient mouse strains, such as NOD/Shi-scid IL2rg null (NOG) (17)(18)(19), NOD/LtSz-scid IL2rg null (NSG) (20), and BALB/c Rag2 null IL2rg null (21,22), enabled long-term engraftment of human tissues because of the total lack of the endogenous mouse immune system, enormously improving the generation of humanized mice.…”

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confidence: 99%

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

Ito

Takahashi

Katano

et al. 2013

The Journal of Immunology

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133

128

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The development of animal models that mimic human allergic responses is crucial to study the pathophysiology of disease and to generate new therapeutic methodologies. Humanized mice reconstituted with human immune systems are essential to study human immune reactions in vivo and are expected to be useful for studying human allergies. However, application of this technology to the study of human allergies has been limited, largely because of the poor development of human myeloid cells, especially granulocytes and mast cells, which are responsible for mediating allergic diseases, in conventional humanized mice. In this study, we developed a novel transgenic (Tg) strain, NOD/Shi-scid-IL2rγnull (NOG), bearing human IL-3 and GM-CSF genes (NOG IL-3/GM–Tg). In this strain, a large number of human myeloid cells of various lineages developed after transplantation of human CD34+ hematopoietic stem cells. Notably, mature basophils and mast cells expressing FcεRI were markedly increased. These humanized NOG IL-3/GM–Tg mice developed passive cutaneous anaphylaxis reactions when administered anti–4-hydroxy-3-nitrophenylacetyl IgE Abs and 4-hydroxy-3-nitrophenylacetyl. More importantly, a combination of serum from Japanese cedar pollinosis patients and cedar pollen extract also elicited strong passive cutaneous anaphylaxis responses in mice. Thus, to our knowledge, our NOG IL-3/GM–Tg mice are the first humanized mouse model to enable the study of human allergic responses in vivo and are excellent tools for preclinical studies of allergic diseases.

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Remarkable Lethal G-to-A Mutations in vif- Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice

Cited by 78 publications

References 62 publications

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

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