Resistance is futile: Assimilation of cellular machinery by HIV-1

Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305, USA.
Immunity (Impact Factor: 21.56). 12/2001; 15(5):687-90. DOI: 10.1016/S1074-7613(01)00238-2
Source: PubMed


HIV-1 budding appears to require Vps4 and Tsg101-two proteins that have links to endosomal sorting machinery. A picture emerges wherein divergent viruses recruit endosomal proteins like Tsg101 to gain access to ubiquitin processes that play a crucial role during viral budding.

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    • "A possible explanation for the success of Grande proliferation is the likely role of the nuclear targeted gene23-encoded protein (Fig. 4) in helping the pre-integration complex to entry in the nucleus of non-dividing cells. LTR retrotransposons' life cycle shares some sequential steps with their close relatives, the retroviruses: the transcription of an integrated DNA, the nuclear export to cytoplasm of retroelements' transcripts, the mRNA translation and particle formation, and the reverse transcription and integration [for a review, see (Perez and Nolan 2001; Havecker et al. 2004)]. However, retroviruses have at least two additional steps between particle formation and the reverse transcription which give them infectivity: the budding out the cell (and proteolytic maturation) and the virion entry into a new cell and partial uncoating (Nisole and Saı¨b 2004). "
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    ABSTRACT: LTR retrotransposons are major components of plant genomes playing important roles in the evolution of their host genomes, for example, generating new genes or providing new promoters to existing genes. The Grande family of retrotransposons is present in Zea species and is characterized by an unusually long internal region due to the presence of a 7-kbp region between the gag-pol coding region and the 3'LTR. We demonstrate here that such unusual sequence is present in the great majority of Grande copies in maize genome. This region contains a gene, gene23, which is transcribed from its own promoter in antisense orientation to the gag-pol genes. The expression of gene23 is ubiquitous, and its promoter contains all the putative consensus sequences typical of eukaryotic promoters, being able to direct GUS expression in different plant species and organs. The coding region of gene23 is conserved in most Grande copies and encodes a protein rich in glycine, serine, and acidic amino acids that shows no significant similarity with any protein of known function. Nevertheless, the C- and N-terminal parts are rich in basic amino acids, and these are interspersed with other amino acids in its C-terminus, compatible with a putative DNA-binding function. It contains a nuclear localization signal KRKR motif in the N-terminus. Fusions to GFP demonstrate that this protein localizes in the nucleus. We discuss the possible origin of gene23 and the potential function of its encoded protein.
    Plant Molecular Biology 02/2013; 81(6). DOI:10.1007/s11103-013-0019-2 · 4.26 Impact Factor
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    • "A number of studies have reported that endocytosis may be one prominent route for HIV entry into its target cells [127–129] and this mode of virus entry was suggested to take place in the VS [3]. The lateral sorting of TCR into the cSMAC is mediated by endosomal sorting complexes required for transport (ESCRT) component TSG101 [52], which also plays a role in the viral budding machinery [53–56]. Furthermore, bidirectional membrane trafficking has been demonstrated in the activating natural killer cell synapse [130]. "
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    ABSTRACT: The virological synapse (VS) is a tight adhesive junction between an HIV-infected cell and an uninfected target cell, across which virus can be efficiently transferred from cell to cell in the absence of cell-cell fusion. The VS has been postulated to resemble, in its morphology, the well-studied immunological synapse (IS). This review article discusses the structural similarities between IS and VS and the shared T cell receptor (TCR) signaling components that are found in the VS. However, the IS and the VS display distinct kinetics in disassembly and intracellular signaling events, possibly leading to different biological outcomes. Hence, HIV-1 exploits molecular components of IS and TCR signaling machinery to trigger unique changes in cellular morphology, migration, and activation that facilitate its transmission and cell-to-cell spread.
    Viruses 05/2010; 2(5):1239-60. DOI:10.3390/v2051239 · 3.35 Impact Factor
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    • "Enveloped viruses encounter the opposite situation than that of internalized membrane proteins since they are assembled inside the cell but need to transit to and through the cell membrane [15] [16]. Consequently, many viruses have converged upon a mechanism by which the function of TSG101 is " hijacked " in a manner that facilitates a retrograde movement of viruses from the cell interior to the outer membrane [16]. Indeed, a welldeveloped literature has demonstrated that TSG101 plays an essential role in the viral life cycle and that this role is independent of its normal role in proteosomal transport [21]. "
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    ABSTRACT: The treatment of viral diseases remains an intractable problem facing the medical community. Conventional antivirals focus upon selective targeting of virus-encoded targets. However, the plasticity of viral nucleic acid mutation, coupled with the large number of progeny that can emerge from a single infected cells, often conspire to render conventional antivirals ineffective as resistant variants emerge. Compounding this, new viral pathogens are increasingly recognized and it is highly improbable that conventional approaches could address emerging pathogens in a timely manner. Our laboratories have adopted an orthogonal approach to combat viral disease: Target the host to deny the pathogen the ability to cause disease. The advantages of this novel approach are many-fold, including the potential to identify host pathways that are applicable to a broad-spectrum of pathogens. The acquisition of drug resistance might also be minimized since selective pressure is not directly placed upon the viral pathogen. Herein, we utilized this strategy of host-oriented therapeutics to screen small molecules for their abilities to block infection by multiple, unrelated virus types and identified FGI-104. FGI-104 demonstrates broad-spectrum inhibition of multiple blood-borne pathogens (HCV, HBV, HIV) as well as emerging biothreats (Ebola, VEE, Cowpox, PRRSV infection). We also demonstrate that FGI-104 displays an ability to prevent lethality from Ebola in vivo. Altogether, these findings reinforce the concept of host-oriented therapeutics and present a much-needed opportunity to identify antiviral drugs that are broad-spectrum and durable in their application.
    American Journal of Translational Research 05/2009; 1(1):87-98. DOI:10.1016/j.antiviral.2009.02.082 · 3.40 Impact Factor
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