Generation of human TRIM5α mutants with high HIV-1 restriction activity

Pham, Quang Toan; Bouchard, Amélie; Grütter, Markus G.; Berthoux, Lionel

doi:10.1038/gt.2010.40

Cited by 52 publications

(84 citation statements)

References 74 publications

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“…Numerous mutations within the loop are known to disrupt restriction, and conversely, mutations within the v1 of the human TRIM5α can restore HIV restriction with potency approaching that of the rhesus protein (12,22,23). Moreover, the composition of the v1 loop has been under strong positive selection during recent primate evolution (13).…”

Section: Resultsmentioning

confidence: 99%

“…Just as in the case of antigen-antibody interactions, TRIM5α mutations that affect binding are not necessarily altering direct contacts with the ligand, but rather may act by limiting the conformational space accessible to the v1 variable loop segment. For example, v1 dynamics may help explain how point mutations within the v1 of the human TRIM5α can alter its viral specificity profile or restore its activity against HIV (12,22,23,35,36).…”

Section: Discussionmentioning

confidence: 99%

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Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Biris¹,

Yang

Taylor³

et al. 2012

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

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Tripartite motif protein TRIM5α blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/ PRYSPRY domain. Here we report a high-resolution structure of a TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRI-M5α that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsidbinding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5α evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5α. Distinctive features of this pathogenrecognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Biris¹,

Yang

Taylor³

et al. 2012

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

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show abstract

“…The V1 loop contains many important residues in retroviral capsid interaction, and its flexibility may allow these residues to recognize various viral capsids of different shapes (discussed below). Regardless of the conformation of the V1 loop, some critical residues (residues 332, 335, and 336 of huTRIM5α) that confer restriction specificity (15,16,33,34) are located in the middle of V1. This location could place the residues at the tip of the V1 loop when it is extended ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Yang

Zhao

et al. 2012

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

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Tripartite motif protein isoform 5 alpha (TRIM5α) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses. TRIM5α recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner. Upon binding, TRIM5α induces premature disassembly of the viral capsid and activates the downstream innate immune response. We have determined the crystal structure of the rhesus TRIM5α PRY/ SPRY domain that reveals essential features for capsid binding. Combined cryo-electron microscopy and biochemical data show that the monomeric rhesus TRIM5α PRY/SPRY, but not the human TRIM5α PRY/SPRY, can bind to HIV-1 capsid protein assemblies without causing disruption of the capsid. This suggests that the PRY/SPRY domain alone constitutes an important pattern-sensing component of TRIM5α that is capable of interacting with viral capsids of different curvatures. Our results provide molecular insights into the mechanisms of TRIM5α-mediated retroviral restriction.

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“…The size of the 32-amino-acid extension (ϳ50 Å) in the v2 loop, comparable to the size of the core structure of B30.2/SPRY (40 to 50 Å), matches the dimensions of an HIV-1 capsid monomer (45 by 35 by 22 Å). The unique breadth of restriction conferred by v2 could be attractive in human gene therapy applications (43). Another remarkable aspect of lemur TRIM5␣ is the pattern of activity against gammaretroviruses.…”

Section: Discussionmentioning

confidence: 99%

Unique Spectrum of Activity of Prosimian TRIM5α against Exogenous and Endogenous Retroviruses

Rahm

Yap²,

Snoeck

et al. 2011

J Virol

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Lentiviruses, the genus of retrovirus that includes HIV-1, rarely endogenize. Some lemurs uniquely possess an endogenous lentivirus called PSIV ("prosimian immunodeficiency virus"). Thus, lemurs provide the opportunity to study the activity of host defense factors, such as TRIM5␣, in the setting of germ line invasion. We characterized the activities of TRIM5␣ proteins from two distant lemurs against exogenous retroviruses and a chimeric PSIV. TRIM5␣ from gray mouse lemur, which carries PSIV in its genome, exhibited the narrowest restriction activity.

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Generation of human TRIM5α mutants with high HIV-1 restriction activity

Cited by 52 publications

References 74 publications

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Unique Spectrum of Activity of Prosimian TRIM5α against Exogenous and Endogenous Retroviruses

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