Trim5α Accelerates Degradation of Cytosolic Capsid Associated with Productive HIV-1 Entry

Chatterji, Udayan; Bobardt, Michael; Gaskill, Peter J.; Sheeter, Dennis A.; Fox, Howard S.; Gallay, Philippe

doi:10.1074/jbc.m606066200

Cited by 51 publications

(41 citation statements)

References 44 publications

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“…While the proteasome might not degrade the RNA directly, we imagine that degradation of the virion protein would render the genome sensitive to degradation by cellular nucleases. These observations are inconsistent with an uncoating mechanism for TRIM5␣, which might be expected to increase the release of the genome and RMT (5,22,23). Finally, our use of retroviral vectors which cannot reverse transcribe due to modification of the PBS demonstrates that sensitivity to TRIM5␣ and proteasomal degradation of the mRNA do not depend on the initiation of RT.…”

Section: Discussioncontrasting

confidence: 45%

“…Since MG132 increases the efficiency of lentiviral infection in a cell type-dependent manner (27), we examined the influence of MG132 on restricted particles in comparison to its influence on nonrestricted particles. To minimize unspecific toxicity, we used MG132 at a relatively low concentration (0.5 mol/liter), which is at least four times lower than the concentration used in related studies on retroviral restriction (5,29). Both the RT-proficient (iRV) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

Galla

Schambach

Towers³

et al. 2008

J Virol

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Analyzing cellular restriction mechanisms provides insight into viral replication strategies, identifies targets for antiviral drug design, and is crucial for the development of novel tools for experimental or therapeutic delivery of genetic information. We have previously shown that retroviral vector mutants that are unable to initiate reverse transcription mediate a transient expression of any sequence which replaces the gag-pol transcription unit, a process we call retrovirus particle-mediated mRNA transfer (RMT). Here, we further examined the mechanism of RMT by testing its sensitivity to cellular restriction factors and short hairpin RNAs (shRNAs). We found that both human TRIM5␣ and, to a lesser extent, Fv1 effectively restrict RMT if the RNA is delivered by a restriction-sensitive capsid. While TRIM5␣ restriction of RMT led to reduced levels of retroviral mRNA in target cells, restriction by Fv1 did not. Treatment with the proteasome inhibitor MG132 partially relieved TRIM5␣-mediated restriction of RMT. Finally, cells expressing shRNAs specifically targeting the retroviral mRNA inhibited RMT particles, but not reverse-transcribing particles. Retroviral mRNA may thus serve as a translation template if not used as a template for reverse transcription. Our data imply that retroviral nucleic acids become accessible to host factors, including ribosomes, as a result of particle remodeling during cytoplasmic trafficking.Retroviruses enter cells in a receptor-mediated manner, following which a reverse transcription (RT) complex is formed in the cytoplasm to reverse transcribe the genomic mRNA into double-stranded DNA. During the completion of RT, a hybrid virus-cellular nucleoprotein structure known as the preintegration complex (PIC) is formed. Eventually, active transport of the PIC into the nucleus or dissolution of the nuclear membrane during mitosis allows the viral integrase to integrate the viral double-stranded DNA into chromosomal cellular DNA (35). We have previously shown that retroviral vector mutants that are unable to initiate RT of their capped, plus-stranded mRNA genomes mediate a transient expression of the sequences cloned into the gag-pol-equivalent position of the vector genome (8). Particles conferring this activity required the presence of the retroviral mRNA packaging signal within the vector sequence, as well as the expression of both Gag and Env in the vector packaging cell, but not reverse transcriptase. We refer to this previously unexplored aspect of the retrovirus life cycle as retrovirus particle-mediated mRNA transfer (RMT). Using replication-defective retroviral vectors in which the gene of interest is cloned in the position of the gag reading frame, RMT can be exploited as a novel approach for the transient expression of a gene of interest (8).The analysis of cellular restriction factors that belong to the innate immune response against retroviruses may provide further insights into the mechanisms of RMT. The cellular restriction factor Fv1 (Friend virus susceptibility factor 1) h...

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Section: Discussioncontrasting

confidence: 45%

Section: Resultsmentioning

confidence: 99%

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

Galla

Schambach

Towers³

et al. 2008

J Virol

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“…This work also found that the rhTRIM5a-mediated degradation of capsid was independent of proteasome function, as proteasome inhibitors did not prevent capsid degradation measured in these experiments. 57 These data form a model in which the stripping of capsid protein from the viral nucleoprotein complexes prevents the complex from completing subsequent steps in the infectious pathway.…”

Section: Proteasome Independent Capsid Degradationmentioning

confidence: 99%

“…57 This work separated cytosolic and vesicular fractions from cells infected with HIV-1 and found that cells expressing rhTRIM5a induced the degradation of viral capsid without affecting other components of the viral nucleoprotein complex. This work also found that the rhTRIM5a-mediated degradation of capsid was independent of proteasome function, as proteasome inhibitors did not prevent capsid degradation measured in these experiments.…”

Section: Proteasome Independent Capsid Degradationmentioning

confidence: 99%

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

Sastri

Campbell

2011

AIDS Research and Human Retroviruses

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The cellular factor TRIM5a inhibits infection by numerous retroviruses in a species-specific manner. The TRIM5a protein from rhesus macaques (rhTRIM5a) restricts infection by HIV-1 while human TRIM5a (huTRIM5a) restricts infection by murine leukemia virus (MLV). In owl monkeys a related protein TRIM-Cyp restricts HIV-1 infection. Several models have been proposed for retroviral restriction by TRIM5 proteins (TRIM5a and TRIMCyp). These models collectively suggest that TRIM5 proteins mediate restriction by directly binding to specific determinants in the viral capsid. Through their ability to self-associate TRIM5 proteins compartmentalize the viral capsid core and mediate its abortive disassembly via a poorly understood mechanism that is sensitive to proteasome inhibitors. In this review, we discuss TRIM5-mediated restriction in detail. We also discuss how polymorphisms within human and rhesus macaque populations have been demonstrated to affect disease progression of immunodeficiency viruses in these species.

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“…Trim5α and its derivative TRIMCyp restrict HIV-1 infection at early steps of the viral life cycle in a speciesspecific manner (6,7). Trim5α mediates the degradation of the capsid (CA) protein of HIV-1 through its ubiquitin E3 ligase activity (8). There is also evidence showing that Trim5α induces rapid uncoating of the HIV-1 capsid, resulting in failure to form a functional preintegration complex (6,9).…”

mentioning

confidence: 99%

Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation

Zhu

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

262

337

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The zinc-finger antiviral protein (ZAP) was originally identified as a host factor that inhibits the replication of Moloney murine leukemia virus. Here we report that ZAP inhibits HIV-1 infection by promoting the degradation of specific viral mRNAs. Overexpression of ZAP rendered cells resistant to HIV-1 infection in a ZAP expression level-dependent manner, whereas depletion of endogenous ZAP enhanced HIV-1 infection. Both human and rat ZAP inhibited the propagation of replication-competent HIV-1. ZAP specifically targeted the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 39 end. In addition, ZAP recruits cellular decapping complex through its cofactor RNA helicase p72 to initiate degradation of the target viral mRNA from the 59 end. Depletion of each of these mRNA degradation enzymes reduced ZAP's activity. Our results indicate that ZAP inhibits HIV-1 by recruiting both the 59 and 39 mRNA degradation machinery to specifically promote the degradation of multiply spliced HIV-1 mRNAs.retrovirus | host restriction factor | RNA degradation

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Trim5α Accelerates Degradation of Cytosolic Capsid Associated with Productive HIV-1 Entry

Cited by 51 publications

References 44 publications

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation

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