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1.
James Curlin Kimberly Schmitt Leila Remling-Mulder Ryan Moriarty Mark Stenglein Shelby O'Connor Preston Marx Ramesh Akkina 《Journal of medical primatology》2020,49(1):40-43
HIV-1 evolved from its progenitor SIV strains, but details are lacking on its adaptation to the human host. We followed the evolution of SIVcpz in humanized mice to mimic cross-species transmission. Increasing viral loads, CD4+ T-cell decline, and non-synonymous mutations were seen in the entire genome reflecting viral adaptation. 相似文献
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Kimberly Schmitt James Curlin Leila Remling-Mulder Ryan Moriarty Kelly Goff Shelby O’Connor Mark Stenglein Preston Marx Ramesh Akkina 《Journal of medical primatology》2020,49(5):284-287
HIV-1 evolved from SIV during cross-species transmission events, though viral genetic changes are not well understood. Here, we studied the evolution of SIVcpzLB715 into HIV-1 Group M using humanized mice. High viral loads, rapid CD4+ T-cell decline, and non-synonymous substitutions were identified throughout the viral genome suggesting viral adaptation. 相似文献
3.
Ikumi Katano Ryoji Ito Tsutomu Kamisako Tomoo Eto Tomoyuki Ogura Kenji Kawai Hiroshi Suemizu Takeshi Takahashi Yutaka Kawakami Mamoru Ito 《Experimental Animals》2014,63(3):321-330
We have developed NOD-Rag2null IL-2Rγnull (NR2G)
mice similar to NOD-scidIL-2Rγnull (NOG) mice
that are known as an excellent host to generate humanized mice. To evaluate the usefulness
of NR2G mice as a host for humanized mice, the engraftment rates and differentiation of
human cells after human hematopoietic stem cell (HSC) transplantation were compared among
NR2G, NOG, and NOD-scid mice. For this purpose, the appropriate
irradiation doses to expand the niche for human stem cells in the bone marrow were first
determined. As a result, 8 and 2.5 Gy in adult, and 4 and 1 Gy in newborn NR2G and NOG
mice, respectively, were found to be appropriate. Next, 5 × 104 human umbilical
cord blood CD34+ cells were intravenously inoculated into irradiated adult or
newborn of the immunodeficient mice. These HSC transplantation experiments demonstrated
that both NR2G and NOG mice showed high engraftment rates compared with
NOD-scid mice, although NOG mice showed a slightly higher engraftment
rate than that for NR2G mice. However, no difference was found in the human cell
populations differentiated from HSCs between NR2G and NOG mice. The HSC transplantation
experiments to adults and newborns of two immunodeficient mice also revealed that the HSC
transplantation into newborn mice resulted in higher engraftment rate than those into
adults. These results showed that NR2G mice could be used as an alternative host to NOG
mice to generate humanized mice. 相似文献
4.
The role of recombination in evolutionary adaptation of Escherichia coli to a novel nutrient 下载免费PDF全文
The benefits and detriments of recombination for adaptive evolution have been studied both theoretically and experimentally, with conflicting predictions and observations. Most pertinent experiments examine recombination's effects in an unchanging environment and do not study its genomewide effects. Here, we evolved six replicate populations of either highly recombining R+ or lowly recombining R? E. coli strains in a changing environment, by introducing the novel nutrients L‐arabinose or indole into the environment. The experiment's ancestral strains are not viable on these nutrients, but 130 generations of adaptive evolution were sufficient to render them viable. Recombination conferred a more pronounced advantage to populations adapting to indole. To study the genomic changes associated with this advantage, we sequenced the genomes of 384 clones isolated from selected replicates at the end of the experiment. These genomes harbour complex changes that range from point mutations to large‐scale DNA amplifications. Among several candidate adaptive mutations, those in the tryptophanase regulator tnaC stand out, because the tna operon in which it resides has a known role in indole metabolism. One of the highly recombining populations also shows a significant excess of large‐scale segmental DNA amplifications that include the tna operon. This lineage also shows a unique and potentially adaptive combination of point mutations and DNA amplifications that may have originated independently from one another, to be joined later by recombination. Our data illustrate that the advantages of recombination for adaptive evolution strongly depend on the environment and that they can be associated with complex genomic changes. 相似文献
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The appearance of human immunodeficiency virus type 1 (HIV-1) plasma viremia is associated with progression to symptomatic disease and CD4+ T cell depletion. To locate the source of systemic viremia, this study employed a novel method to trace HIV-1 infection in vivo. We created JRCSFξnef, a pool of infectious HIV-1 (strain JR-CSF) with highly mutated nef gene regions by random mutagenesis PCR and infected this mutated virus pool into both Jurkat-CCR5 cells and hematopoietic stem cell-transplanted humanized mice. Infection resulted in systemic plasma viremia in humanized mice and viral RNA sequencing helped us to identify multiple lymphoid organs such as spleen, lymph nodes, and bone marrow but not peripheral blood cells as the source of systemic viremia. Our data suggest that this method could be useful for the tracing of viral trafficking in vivo. 相似文献
7.
Zhiwei Chen Paul Telfer Patricia Reed Linqi Zhang Agegnehu Getti David D. Ho Preston A. Marx 《Journal of medical primatology》1995,24(3):108-115
Abstract: The lineage of HIV-2-like viruses was studied in feral sooty mangabeys (SMs) by serological and genetic methods. Four feral sooty mangabeys were positive for simian immunodeficiency virus (SIV) antibodies and a new isolate, SIVsmSL92a, was obtained. Genetic analysis of gag genes showed that SIVsmSL92a was highly diverse and a distinct sequence subtype within the SIVsm/HIV-2 family. The results showed that SIVsm is the most diverse group of SIVs found thus far in a single monkey species. 相似文献
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Salma Nowroozalizadeh Fredrik Mnsson Zacarias da Silva Johanna Repits Braima Dabo Carla Pereira Antonio Biague Jan Albert Jens Nielsen Peter Aaby Eva Maria Feny Hans Norrgren Birgitta Holmgren Marianne Jansson 《Cytokine》2009,46(3):325-331
Background: HIV-1 and HIV-2 are two related viruses with distinct clinical outcomes, where HIV-1 is more pathogenic and transmissible than HIV-2. The pathogenesis of both infections is influenced by the dysregulation and deterioration of the adaptive immune system. However, their effects on the responsiveness of innate immunity are less well known. Here, we report on toll-like receptor (TLR) stimuli responsiveness in HIV-1 or HIV-2 infections. Methods: Whole blood from 235 individuals living in Guinea-Bissau who were uninfected, infected with HIV-1, infected with HIV-2, and/or infected with HTLV-I, was stimulated with TLR7/8 and TLR9 agonists, R-848 and unmethylated CpG DNA. After TLR7/8 and TLR9 stimuli, the expression levels of IL-12 and IFN-α were related to gender, age, infection status, CD4+ T cell counts, and plasma viral load. Results: Defective TLR9 responsiveness was observed in the advanced disease stage, along with CD4+ T cell loss in both HIV-1 and HIV-2 infections. Moreover, TLR7/8 responsiveness was reduced in HIV-1 infected individuals compared with uninfected controls. Conclusions: Innate immunity responsiveness can be monitored by whole blood stimulation. Both advanced HIV-1 and HIV-2 infections may cause innate immunity dysregulation. 相似文献
10.
Masaaki Arai Yuko Tokunaga Asako Takagi Yoshimi Tobita Yuichi Hirata Yuji Ishida Chise Tateno Michinori Kohara 《PloS one》2013,8(12)
Multiple genotype 1a clones have been reported, including the very first hepatitis C virus (HCV) clone called H77. The replication ability of some of these clones has been confirmed in vitro and in vivo, although this ability is somehow compromised. We now report a newly isolated genotype 1a clone, designated HCV-RMT, which has the ability to replicate efficiently in patients, chimeric mice with humanized liver, and cultured cells. An authentic subgenomic replicon cell line was established from the HCV-RMT sequence with spontaneous introduction of three adaptive mutations, which were later confirmed to be responsible for efficient replication in HuH-7 cells as both subgenomic replicon RNA and viral genome RNA. Following transfection, the HCV-RMT RNA genome with three adaptive mutations was maintained for more than 2 months in HuH-7 cells. One clone selected from the transfected cells had a high copy number, and its supernatant could infect naïve HuH-7 cells. Direct injection of wild-type HCV-RMT RNA into the liver of chimeric mice with humanized liver resulted in vigorous replication, similar to inoculation with the parental patient’s serum. A study of virus replication using HCV-RMT derivatives with various combinations of adaptive mutations revealed a clear inversely proportional relationship between in vitro and in vivo replication abilities. Thus, we suggest that HCV-RMT and its derivatives are important tools for HCV genotype 1a research and for determining the mechanism of HCV replication in vitro and in vivo. 相似文献
11.
Spencer Benson 《BioEssays : news and reviews in molecular, cellular and developmental biology》1997,19(1):9-11
A recent article by Galitski and Roth(1) characterizes adaptive reversion of chromosomal lac? mutations in Salmonella typhimurium LT2. Using a classical genetic approach they show that adaptive reversion, as characterized by the appearance of late revertant colonies, is an exception rather than a general phenomenon for reversion of nonsense, missense, frameshift and insertion mutations. For certain mutations, however, the number of late revertants exceeds the predicted number. These excess revertants suggest that adaptive mutability is applicable to chromosomal genes as well as to genetic changes involving F plasmids and lysogenic phages. 相似文献
12.
De-Kuan Chang Vinodh B. Kurella Subhabrata Biswas Yuval Avnir Jianhua Sui Xueqian Wang 《MABS-AUSTIN》2016,8(4):787-798
In 10–20% of the cases of chronic lymphocytic leukemia of B-cell phenotype (B-CLL), the IGHV1-69 germline is utilized as VH gene of the B cell receptor (BCR). Mouse G6 (MuG6) is an anti-idiotypic monoclonal antibody discovered in a screen against rheumatoid factors (RFs) that binds with high affinity to an idiotope expressed on the 51p1 alleles of IGHV1-69 germline gene encoded antibodies (G6-id+). The finding that unmutated IGHV1-69 encoded BCRs are frequently expressed on B-CLL cells provides an opportunity for anti-idiotype monoclonal antibody immunotherapy. In this study, we first showed that MuG6 can deplete B cells encoding IGHV1-69 BCRs using a novel humanized GTL mouse model. Next, we humanized MuG6 and demonstrated that the humanized antibodies (HuG6s), especially HuG6.3, displayed ~2-fold higher binding affinity for G6-id+ antibody compared to the parental MuG6. Additional studies showed that HuG6.3 was able to kill G6-id+ BCR expressing cells and patient B-CLL cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, both MuG6 and HuG6.3 mediate in vivo depletion of B-CLL cells in NSG mice. These data suggest that HuG6.3 may provide a new precision medicine to selectively kill IGHV1-69-encoding G6-id+ B-CLL cells. 相似文献
13.
Manel Camps Asael Herman Ern Loh Lawrence A. Loeb 《Critical reviews in biochemistry and molecular biology》2013,48(5):313-326
ABSTRACTEvolution requires the generation and optimization of new traits (“adaptation”) and involves the selection of mutations that improve cellular function. These mutations were assumed to arise by selection of neutral mutations present at all times in the population. Here we review recent evidence that indicates that deleterious mutations are more frequent in the population than previously recognized and that these mutations play a significant role in protein evolution through continuous positive selection. Positively selected mutations include adaptive mutations, i.e. mutations that directly affect enzymatic function, and compensatory mutations, which suppress the pleiotropic effects of adaptive mutations. Compensatory mutations are by far the most frequent of the two and would allow potentially adaptive but deleterious mutations to persist long enough in the population to be positively selected during episodes of adaptation. Compensatory mutations are, by definition, context-dependent and thus constrain the paths available for evolution. This provides a mechanistic basis for the examples of highly constrained evolutionary landscapes and parallel evolution reported in natural and experimental populations. The present review article describes these recent advances in the field of protein evolution and discusses their implications for understanding the genetic basis of disease and for protein engineering in vitro. 相似文献
14.
Stéphanie Beaucourt Antonio V. Bordería Lark L. Coffey Nina F. Gn?dig Marta Sanz-Ramos Yasnee Beeharry Marco Vignuzzi 《Journal of visualized experiments : JoVE》2011,(52)
RNA viruses use RNA dependent RNA polymerases to replicate their genomes. The intrinsically high error rate of these enzymes is a large contributor to the generation of extreme population diversity that facilitates virus adaptation and evolution. Increasing evidence shows that the intrinsic error rates, and the resulting mutation frequencies, of RNA viruses can be modulated by subtle amino acid changes to the viral polymerase. Although biochemical assays exist for some viral RNA polymerases that permit quantitative measure of incorporation fidelity, here we describe a simple method of measuring mutation frequencies of RNA viruses that has proven to be as accurate as biochemical approaches in identifying fidelity altering mutations. The approach uses conventional virological and sequencing techniques that can be performed in most biology laboratories. Based on our experience with a number of different viruses, we have identified the key steps that must be optimized to increase the likelihood of isolating fidelity variants and generating data of statistical significance. The isolation and characterization of fidelity altering mutations can provide new insights into polymerase structure and function1-3. Furthermore, these fidelity variants can be useful tools in characterizing mechanisms of virus adaptation and evolution4-7. 相似文献
15.
Artur Schuller Monika Cserjan-Puschmann Christoph Köppl Reingard Grabherr Martin Wagenknecht Matteo Schiavinato Juliane C. Dohm Heinz Himmelbauer Gerald Striedner 《Biotechnology journal》2021,16(3):2000376
The production of recombinant proteins usually reduces cell fitness and the growth rate of producing cells. The growth disadvantage favors faster-growing non-producer mutants. Therefore, continuous bioprocessing is hardly feasible in Escherichia coli due to the high escape rate. The stability of E. coli expression systems under long-term production conditions and how metabolic load triggered by recombinant gene expression influences the characteristics of mutations are investigated. Iterated fed-batch-like microbioreactor cultivations are conducted under production conditions. The easy-to-produce green fluorescent protein (GFP) and a challenging antigen-binding fragment (Fab) are used as model proteins, and BL21(DE3) and BL21Q strains as expression hosts. In comparative whole-genome sequencing analyses, mutations that allowed cells to grow unhindered despite recombinant protein production are identified. A T7 RNA polymerase expression system is only conditionally suitable for long-term cultivation under production conditions. Mutations leading to non-producers occur in either the T7 RNA polymerase gene or the T7 promoter. The host RNA polymerase-based BL21Q expression system remains stable in the production of GFP in long-term cultivations. For the production of Fab, mutations in lacI of the BL21Q derivatives have positive effects on long-term stability. The results indicate that adaptive evolution carried out with genome-integrated E. coli expression systems in microtiter cultivations under industrial-relevant production conditions is an efficient strain development tool for production hosts. 相似文献
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Insights from mouse models of absence epilepsy into Ca2+ channel physiology and disease etiology 总被引:3,自引:0,他引:3
Felix R 《Cellular and molecular neurobiology》2002,22(2):103-120
1. Changes in intracellular Ca2+ ([Ca2+]i) levels provide signals that allow neurons to respond to a host of external stimuli. A major mechanism for elevating Ca2+ ([Ca2+]i) is the influx of extracellular Ca2+ through voltage-gated channels (CaV) in the plasma membrane. in CaV due to mutations in genes encoding channel proteins are increasingly being implicated in causing disease conditions, termed channelopathies.2. Seven spontaneous mutations with cerebellar ataxia and generalized absence epilepsy have been identified in mice (tottering, leaner, rolling Nagoya, rocker, lethargic, ducky, and stargazer), and these overlapping phenotypes are directly related to mutations in genes encoding the four separate subunits that together form the multimeric neuronal CaV complex.3. The discovery and systematic analysis of these animal models is helping to clarify how different mutations affect channel function and how altered channel function produces disease. 相似文献
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Shenggen Yao Allan M. Torres Ahmed A. Azad Ian G. Macreadie Raymond S. Norton 《Journal of peptide science》1998,4(7):426-435
Vpr, one of the accessory gene products encoded by HIV-1, is a 96-residue protein with a number of functions, including targeting of the viral pre-integration complex to the nucleus and inducing growth arrest of dividing cells. We have characterized by 2D NMR the solution conformations of bioactive synthetic peptide fragments of Vpr encompassing a pair of H(F/S)RIG sequence motifs (residues 71–75 and 78–82 of HIV-1 Vpr) that cause cell membrane permeabilization and death in yeast and mammalian cells. Due to limited solubility of the peptides in water, their structures were studied in aqueous trifluoroethanol. Peptide Vpr59–86 (residues 59–86 of Vpr) formed an α-helix encompassing residues 60–77, with a kink in the vicinity of residue 62. The first of the repeated sequence motifs (HFRIG) participated in the well-defined α-helical domain whereas the second (HSRIG) lay outside the helical domain and formed a reverse turn followed by a less ordered region. On the other hand, peptides Vpr71–82 and Vpr71–96, in which the sequence motifs were located at the N-terminus, were largely unstructured under similar conditions, as judged by their CαH chemical shifts. Thus, the HFRIG and HSRIG motifs adopt α-helical and turn structures, respectively, when preceded by a helical structure, but are largely unstructured in isolation. The implications of these findings for interpretation of the structure–function relationships of synthetic peptides containing these motifs are discussed. © 1998 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
20.
Suitable animal models for human immunodeficiency virus type 1(HIV-1) infection are important for elucidating viral pathogenesis and evaluating antiviral strategies in vivo. The B-NSG(NOD-PrkdcscidIl2rgtm1/Bcge) mice that have severe immune defect phenotype are examined for the suitability of such a model in this study. Human peripheral blood mononuclear cells(PBMCs) were engrafted into B-NSG mice via mouse tail vein injection, and the repopulated human T-lymphocytes were observed at as early as 3-weeks post-transplantation in mouse peripheral blood and several tissues.The humanized mice could be infected by HIV-1, and the infection recapitulated features of T-lymphocyte dynamic observed in HIV-1 infected humans, meanwhile the administration of combination antiretroviral therapy(cART) suppressed viral replication and restored T lymphocyte abnormalities. The establishment of HIV-1 infected humanized B-NSG mice not only provides a model to study virus and T cell interplays, but also can be a useful tool to evaluate antiviral strategies. 相似文献