A human TRIM5α B30.2/SPRY domain mutant gains the ability to restrict and prematurely uncoat B-tropic murine leukemia virus

Díaz-Griffero, Felipe; Perron, Michel; McGee-Estrada, Kathleen; Hanna, R.E.B.; Maillard, Pierre V; Trono, Didier; Sodroski, Joseph

doi:10.1016/j.virol.2008.05.008

Cited by 65 publications

(84 citation statements)

References 32 publications

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“…3B is larger than the solvent-exposed surface of the capsid N-terminal domain monomer and is likely to recognize epitopes spanning more than one capsid monomer within the hexamer. Such an extended interaction surface with multiple epitopes is consistent with numerous functional studies (28,35,37) and with the analysis of the MLV mutants that escape restriction by TRIM5α (38), which showed that point mutations that compromise restriction are located almost 30 Å apart on the capsid surface.…”

Section: Discussionsupporting

confidence: 87%

“…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%

“…Cf2Th canine thymocytes were transduced with the different constructs and selected in 5 μg∕mL of puromycin (Sigma). Recombinant HIV-1 expressing GFP was prepared as described (35). All recombinant viruses were pseudotyped with the vesicular stomatitis virus G glycoprotein.…”

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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: Discussionsupporting

confidence: 87%

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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“…Recombinant HIV-1 and the HIV-1-G208R mutant expressing green fluorescent protein (GFP) were prepared as described previously (31). Recombinant viruses were pseudotyped with the VSV-G glycoprotein.…”

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confidence: 99%

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

Opp

Vieira

Schulte

et al. 2016

J Virol

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MxB restricts HIV-1 infection by directly interacting with the HIV-1 core, which is made of viral capsid; however, the contribution of MxB to the HIV-1 restriction observed in alpha interferon (IFN-␣)-treated human cells is unknown. To understand this contribution, we used HIV-1 bearing the G208R capsid mutant (HIV-1-G208R), which overcomes the restriction imposed by cells expressing MxB. Here we showed that the reason why MxB does not block HIV-1-G208R is that MxB does not interact with HIV-1 cores bearing the mutation G208R. M yxovirus resistance proteins represent a family of interferon-inducible factors with a wide range of antiviral activities (1-3). The myxovirus B (MxB) gene was originally cloned from a human glioblastoma cell line treated with alpha interferon (IFN-␣) (4, 5). MxB as well as the related protein MxA belong to the dynamin-like family of proteins, which have diverse functions ranging from vesicle transport to antiviral activity (1, 6-11). The most studied dynamin-like protein that exhibits antiviral activity is MxA (1, 2). Contrary to MxB, the antiviral role of MxA has been extensively studied for viruses including influenza virus (1, 12-15), tick-borne Thogoto virus (16), African swine fever virus (17), hepatitis B virus (18), and La Crosse virus (19,20). The antiviral activity of the long form of MxB was recently described (9, 21-23); these investigations led to the discovery that the IFN-␣-inducible protein MxB blocks HIV-1 infection.Genetic evidence suggested that the HIV-1 capsid is the determinant for the ability of MxB to block HIV-1 infection (9,22,23). In agreement with these findings, we recently demonstrated that MxB binds to the HIV-1 capsid and correlated the ability of MxB to block HIV-1 infection with inhibition of uncoating (24). We also showed that the ability of MxB to block infection requires a capsid binding domain and an oligomerization domain provided by the 90 N-terminal and the 143 C-terminal amino acids of MxB, respectively (24). In addition, the work of others and our work showed that the 90 N-terminal amino acids of MxB are important for its ability to bind capsid and restrict HIV-1 infection (24)(25)(26).MxB contains a previously described putative nuclear localization signal on its N-terminal 25 amino acids (4). Deletion of the N-terminal 25 amino acids annihilates the ability of MxB to block HIV-1 infection and to bind to the HIV-1 core (23,24,27). Mutagenic studies have revealed that the N-terminal 25 amino acids of MxB exhibit a triple-arginine motif ( 11 RRR 13 ) that is important for restriction and the ability of MxB to bind to the HIV-1 core (28, 29). HIV-1 CA-NC expression and purification. The CA-NC proteins of HIV-1 and HIV-1 bearing the G208R capsid mutant (HIV-1-G208R) were expressed, purified, and assembled as previously described (30). MATERIALS AND METHODS CellMxB binding to in vitro-assembled HIV-1 and HIV-1-G208R CA-NC complexes. HEK 293T cells were transfected with a plasmid expressing the wild-type MxB protein. Forty-eight hours after t...

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“…For this purpose, we challenged Cf2Th cells with increasing amounts of different retroviruses expressing GFP as reporter of infection (Figure 4 Viruses expressing GFP as a reporter were prepared as previously described [23]. Interestingly, BI-2 potently blocked HIV-1 and SIV mac but not HIV-2 ROD , BIV, FIV, EIAV, N-MLV, B-MLV and Mo-MLV.…”

Section: Ability Of Bi-2 To Block Infection By Different Retrovirusesmentioning

confidence: 99%

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

et al. 2014

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Background: The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74. Findings: This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core. Conclusions: Overall this short-form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection.

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A human TRIM5α B30.2/SPRY domain mutant gains the ability to restrict and prematurely uncoat B-tropic murine leukemia virus

Cited by 65 publications

References 32 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

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

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