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Showing papers by "David Baltimore published in 2012"


Journal ArticleDOI
TL;DR: Recent advances in the understanding of miRNAs and their connection to inflammatory responses are discussed, and the link between perturbations in miRNA levels and the onset of human inflammatory diseases is considered.
Abstract: The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.

802 citations


Journal ArticleDOI
05 Jan 2012-Nature
TL;DR: It is shown that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus, suggesting that successful translation of this approach to humans may produce effective prophylaxis against HIV.
Abstract: Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.

535 citations


Journal ArticleDOI
TL;DR: By suppressing expression of TRAF6 and IRAK1, miR-146a regulates NF-κB activation in T cells through a negative feedback loop and controls the resolution of T cell responses in mice.
Abstract: T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell–mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.

271 citations


Journal ArticleDOI
TL;DR: Since its discovery 25 years ago, nuclear factor‐κB has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory, and both the regulation of their expression and the function of some of the non‐coding RNA genes are discussed.
Abstract: Since its discovery 25 years ago, nuclear factor-κB (NF-κB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF-κB initiates an elaborate genetic program. Some of the NF-κB-driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non-coding RNA genes. We also include a personal discussion of how NF-κB was first discovered.

207 citations


Journal ArticleDOI
TL;DR: This work reveals critical roles for miRNAs in the reciprocal regulation of CD4(+) and CD8(+) T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.

158 citations


Journal ArticleDOI
TL;DR: Investigating the mechanism by which miR-125b regulates hematopoiesis, it was found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR -125b in mouse hematoietic stem and progenitor cells.
Abstract: MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.

144 citations


Journal ArticleDOI
TL;DR: In this article, a microRNA (miRNA), miR-146a, was found to be differentially regulated both in mouse (Ly-6C^(hi)/ Ly-6c^(lo)) and human (CD14^ (hi)/CD14-lo)CD16^+) monocyte subsets.

103 citations


01 Apr 2012
TL;DR: Observations provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6C(hi) monocyte responses while sparing Ly- 6Clo monocyte activity.
Abstract: Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6C^(hi)/Ly-6C^(lo)) and human (CD14^(hi)/CD14^(lo)CD16^+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6C^(hi) monocyte response during inflammatory challenge whereas it did not affect Ly-6C^(lo) cells. miR-146a-mediated regulation was cell-intrinsic and depended on Relb, a member of the noncanonical NF-κB/Rel family, which we identified as a direct miR-146a target. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6C^(hi) monocyte responses while sparing Ly-6C^(lo) monocyte activity.

98 citations


Patent
21 Feb 2012
TL;DR: In this article, compositions, systems and methods for delivery of proteins of interest using adeno-associated virus (AAV) vectors are described, as well as methods for delivering proteins using these vectors.
Abstract: Disclosed herein are compositions, systems and methods for delivery of proteins of interest using adeno-associated virus (AAV) vectors.

96 citations


Journal ArticleDOI
TL;DR: It is demonstrated that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse viral strains, despite repeated exposures, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.
Abstract: The vast majority of new HIV infections result from relatively inefficient transmission1,2 of the virus across mucosal surfaces during sexual intercourse3. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections4. This natural bottleneck to transmission has stimulated efforts to develop interventions aimed at blocking this step of the infection process5. Despite the promise of this strategy, clinical trials of pre-exposure prophylaxis have had limited degrees of success in humans, due in part to lack of adherence to the recommended pre-exposure treatment regimens6,7. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza8 and HPV9. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV using broadly neutralizing antibodies10. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse viral strains, despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain11, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans. Users may view, print, copy, download and text and datamine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Direct all correspondence to: Dr. David Baltimore, California Institute of Technology, Dept. of Biology, M/C:147-75, 1200 E. California Blvd., Pasadena, CA 91125; phone: (626) 395-3580; fax: (626) 585-9495; baltimo@caltech.edu. 2Current address: Ragon Institute of MGH, MIT & Harvard, 400 Technology Sq., Cambridge, MA 02139 Author Contributions A.B.B. and D.B. conceived the study, A.B.B. designed the experiments. D.S.A. offered suggestions for the experiments and provided the BLT humanized mice. A.B.B., Y.O., C.M.H., J.C. and S.M.N. carried out experiments. A.B.B., Y.O., C.M.H., J.C. and S.M.N. analyzed the data. D.S.R. performed immunohistochemistry and analysis. A.B.B. and D.B. wrote the paper with contributions from all authors. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nm. HHS Public Access Author manuscript Nat Med. Author manuscript; available in PMC 2014 September 01. Published in final edited form as: Nat Med. 2014 March ; 20(3): 296–300. doi:10.1038/nm.3471. A uhor M anscript

85 citations


Journal ArticleDOI
29 Nov 2012-Blood
TL;DR: It is shown that the polymeric IgA form of anti-HIV antibody inhibits HIV mucosal transmission more effectively than the monomeric IgA or IgG1 form in a comparable range of concentrations in humanized mice.

Journal ArticleDOI
11 Sep 2012-Mbio
TL;DR: Recovery and sequence of highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims eventually permitted reconstruction of the complete 1918 virus, which has yielded novel insights into influenza virus biology and pathogenesis.
Abstract: The influenza pandemic of 1918–1919 killed approximately 50 million people. The unusually severe morbidity and mortality associated with the pandemic spurred physicians and scientists to isolate the etiologic agent, but the virus was not isolated in 1918. In 1996, it became possible to recover and sequence highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims. These viral RNA sequences eventually permitted reconstruction of the complete 1918 virus, which has yielded, almost a century after the deaths of its victims, novel insights into influenza virus biology and pathogenesis and has provided important information about how to prevent and control future pandemics.

Journal Article
TL;DR: It is shown that the three groups initiate transcription virtually simultaneously but that delays in splicing characterize groups II and III, concluding that pre-mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production.
Abstract: When cells are induced to express inflammatory genes by treatment with TNF, the mRNAs for the induced genes appear in three distinct waves, defining gene groups I, II, and III, or early, intermediate, and late genes. To examine the basis for these different kinetic classes, we have developed a PCR-based procedure to distinguish pre-mRNAs from mRNAs. It shows that the three groups initiate transcription virtually simultaneously but that delays in splicing characterize groups II and III. We also examined the elongation times, concluding that pre-mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production.

Book ChapterDOI
TL;DR: How miRNAs fit into the current understanding of hematopoietic development in mammals and how breakdowns in these pathways can trigger disease are discussed.
Abstract: Hematopoiesis is a dynamic and highly complex developmental process that gives rise to a multitude of the cell types that circulate in the blood of multicellular organisms. These cells provide tissues with oxygen, guard against infection, prevent bleeding by clotting, and mediate inflammatory reactions. Because the hematopoietic system plays such a central role in human diseases such as infections, cancer, autoimmunity, and anemia, it has been intensely studied for more than a century. This scrutiny has helped to shape many of the developmental paradigms that exist today and has identified specific protein factors that serve as master regulators of blood cell lineage specification. Despite this progress, many aspects of blood cell development remain obscure, suggesting that novel layers of regulation must exist. Consequently, the emergence of regulatory noncoding RNAs, such as the microRNAs (miRNAs), is beginning to provide new insights into the molecular control networks underlying hematopoiesis and diseases that stem from aberrations in this process. This review will discuss how miRNAs fit into our current understanding of hematopoietic development in mammals and how breakdowns in these pathways can trigger disease.

Journal ArticleDOI
TL;DR: Some of the possible reasons why HIV persists at different points on the infection timeline are discussed, focusing on the role ongoing replication may have in maintaining the infection despite drugs at early times postexposure.

Journal ArticleDOI
TL;DR: It is reported that a euchromatic H3K9 methyltransferase, EHMT1, functions as a negative regulator in both the NF-κB- and type I interferon-mediated gene induction pathways.

Journal ArticleDOI
20 Sep 2012-Blood
TL;DR: It is shown that the Cap'n'collar member Bach1 regulates the generation of APCs, specifically macrophages and dendritic cells, in mice, and an increase in hematopoietic stem-progenitor cells in these mice is observed, suggesting a developmental block in the progression of HSPCs to CMP-Flk2(+) and subsequently APCs.

Journal ArticleDOI
28 Mar 2012-Vaccine
TL;DR: This study investigated the adjuvanting capacity of glucopyranosyl lipid A (GLA), a chemically synthesized TLR4 agonist, to boost antigen-specific immunity elicited by DC-directed lentiviral vectors (DC-LV) and found that stimulation by this agonist in vitro can activate DCs in aTLR4-dependent manner.

Journal ArticleDOI
28 Nov 2012-PLOS ONE
TL;DR: B12-based Molecular Rheostat constructs promote the maturation of EU12 B cells in an in vitro model of B lymphopoiesis and offers a novel tool for genetically manipulating B cell specificity for B-cell based gene therapy.
Abstract: In nature, B cells produce surface immunoglobulin and secreted antibody from the same immunoglobulin gene via alternative splicing of the pre-messenger RNA. Here we present a novel system for genetically programming B cells to direct the simultaneous formation of membrane-bound and secreted immunoglobulins that we term a “Molecular Rheostat”, based on the use of mutated “self-cleaving” 2A peptides. The Molecular Rheostat is designed so that the ratio of secreted to membrane-bound immunoglobulins can be controlled by selecting appropriate mutations in the 2A peptide. Lentiviral transgenesis of Molecular Rheostat constructs into B cell lines enables the simultaneous expression of functional b12-based IgM-like BCRs that signal to the cells and mediate the secretion of b12 IgG broadly neutralizing antibodies that can bind and neutralize HIV-1 pseudovirus. We show that these b12-based Molecular Rheostat constructs promote the maturation of EU12 B cells in an in vitro model of B lymphopoiesis. The Molecular Rheostat offers a novel tool for genetically manipulating B cell specificity for B-cell based gene therapy.

Patent
18 Jun 2012
TL;DR: In this article, the authors discussed the regulation of macrophage activation by delivering of miRNAs, for example miR-125b or anti-miR- 125b, to macrophages.
Abstract: The present disclosure relates to regulation of macrophage activation by delivering of miRNAs, for example miR-125b or anti-miR-125b, to macrophages. For example, in some embodiments, macrophage activation can be elevated or reduced by administering miR-125b or anti-miR-125b oligonucleotides. Also disclosed are methods for promoting T cell activation and method for treating various disorders such as tumor and autoimmune diseases.


Journal ArticleDOI
30 Mar 2012-Science
TL;DR: A Nobel Prize-winning virologist, Renato Dulbecco discovered a connection between viruses, genetic mutations, and cancer.
Abstract: When a gentle superman passes from our midst, we must bow our heads in recognition of his powers. Renato Dulbecco was both gentle and remarkable. He died on 19 February at his home in La Jolla, California. I got to know Renato when he invited me in 1965 to set up my first laboratory within his space at the then-nascent Salk Institute. He was moving from a professorship at the California Institute of Technology (Caltech), where he already had a notable career in virology. We were to share a Nobel Prize, with Howard Temin, just 10 years later.