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      The Human Immunodeficiency Virus Capsid Is More Than Just a Genome Package

      1 , 2
      Annual Review of Virology
      Annual Reviews

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          Abstract

          Human immunodeficiency virus (HIV) is one of the most studied of all human pathogens. One strain—HIV-1 group M—is responsible for a global pandemic that has infected >60 million people and killed >20 million. Understanding the stages of HIV infection has led to highly effective therapeutics in the form of antiviral drugs that target the viral enzymes reverse transcriptase, integrase, and protease as well as biotechnological developments in the form of retroviral and lentiviral vectors for the transduction of cells in tissue culture and, potentially, gene therapy. However, despite considerable research focus in this area, there is much we still do not understand about the HIV replicative cycle, particularly the first steps that are crucial to establishing a productive infection. One especially enigmatic player has been the HIV capsid. In this review, we discuss three aspects of the HIV capsid: its function as a structural shell, its role in mediating host interactions, and its vulnerability to antiviral activity.

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          Most cited references38

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          The nuclear pore complex: bridging nuclear transport and gene regulation.

          Although the nuclear pore complex (NPC) is best known for its primary function as the key regulator of molecular traffic between the cytoplasm and the nucleus, a growing body of experimental evidence suggests that this structure participates in a considerably broader range of cellular activities on both sides of the nuclear envelope. Indeed, the NPC is emerging as an important regulator of gene expression through its influence on the internal architectural organization of the nucleus and its apparently extensive involvement in coordinating the seamless delivery of genetic information to the cytoplasmic protein synthesis machinery.
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            A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

            Dendritic cells (DC) serve a key function in host defense, linking innate detection of microbes to the activation of pathogen-specific adaptive immune responses(1,2). Whether there is cell-intrinsic recognition of HIV-1 by host innate pattern-recognition receptors and subsequent coupling to antiviral T cell responses is not yet known(3). DC are largely resistant to infection with HIV-1(4), but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement(5,6). We show here that, when DC resistance to infection is circumvented(7,8), HIV-1 induces DC maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly-synthesized HIV-1 capsid (CA) with cellular cyclophilin A (CypA) and the subsequent activation of the transcription factor IRF3. Because the peptidyl-prolyl isomerase CypA also interacts with CA to promote HIV-1 infectivity, our results suggest that CA conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell intrinsic sensor for HIV-1 exists in DC and mediates an antiviral immune response, but it is not typically engaged due to absence of DC infection. The virulence of HIV-1 may be related to evasion of this response, whose manipulation may be necessary to generate an effective HIV-1 vaccine.
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              Intracellular antibody-bound pathogens stimulate immune signaling via Fc-receptor TRIM21

              Antibodies can be carried into the cell during pathogen infection where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we show that TRIM21 recognition of intracellular antibodies activates immune signaling. TRIM21 catalyses K63-ubiquitin chain formation, stimulating transcription factor pathways NF-κB, AP-1 and IRF3, IRF5, IRF7. Activation results in proinflammatory cytokine production, modulation of natural killer (NK) stress ligands and the induction of an antiviral state. Intracellular antibody signaling is abrogated by genetic deletion of TRIM21 and is recovered by ectopic TRIM21 expression. Antibody sensing by TRIM21 can be stimulated upon infection by DNA or RNA non-enveloped viruses or intracellular bacteria. The antibody-TRIM21 detection system provides potent, comprehensive innate immune activation, independent of known pattern recognition receptors.
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                Author and article information

                Journal
                Annual Review of Virology
                Annu. Rev. Virol.
                Annual Reviews
                2327-056X
                2327-0578
                September 29 2018
                September 29 2018
                : 5
                : 1
                : 209-225
                Affiliations
                [1 ]Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;
                [2 ]EMBL Australia Node in Single Molecule Science and ARC Centre of Excellence in Advanced Molecular Imaging, School of Medical Sciences, University of New South Wales Sydney, Randwick NSW 2031, Australia;
                Article
                10.1146/annurev-virology-092917-043430
                746e75b4-02db-4542-b746-70aff4f60eca
                © 2018
                History

                Medicine,Cell biology,Immunology,Human biology,Microbiology & Virology,Life sciences
                Medicine, Cell biology, Immunology, Human biology, Microbiology & Virology, Life sciences

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