Adaptation of HIV-1 to cells expressing rhesus monkey TRIM5α

Pacheco, Beatriz; Finzi, Andrés; Stremlau, Matthew; Sodroski, Joseph

doi:10.1016/j.virol.2010.09.019

Cited by 33 publications

(33 citation statements)

References 66 publications

(107 reference statements)

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“…These would include the CA N-terminal beta hairpin loop, a region C-terminal to helix 4, and the surfaceexposed N-terminal end of helix 6. A similar conclusion has been reached from studies of different lentiviruses (38)(39)(40)(41)(42). Such an extended interaction domain would be consistent with structural studies of the TRIM5␣ PRY-SPRY region that suggest a large, triangular surface region containing the specificity determinants of restriction (25,43,44).…”

Section: Discussionsupporting

confidence: 83%

A Comparison of Murine Leukemia Viruses That Escape from Human and Rhesus Macaque TRIM5αs

Ohkura¹,

Stoye²

2013

J Virol

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To better understand the binding mechanism of TRIM5␣ to retrovirus capsid, we had previously selected N-tropic murine leukemia virus (N-MLV) mutants escaping from rhesus macaque TRIM5␣ (rhTRIM5␣) by passaging the virus in rhTRIM5␣-expressing cells and selecting for nonrestricted variants. To test the commonality of the findings from the rhTRIM5␣ study, we have now employed a similar genetic approach using human TRIM5␣ (huTRIM5␣). Consistent with the rhTRIM5␣ study, the mapped huTRIM5␣ escape mutations were distributed across the capsid exterior, confirming the extended binding surface between virus and restriction factor. Compared to the results of the previous study, fewer escape mutations were identified, with particular mutants being repeatedly selected. Three out four huTRIM5␣ escape variants showed resistance to all primate TRIM5␣s tested, but two of them sacrificed viral fitness, observations that were not made in the rhTRIM5␣ study. Moreover, differences in amino acid changes associated with escape from hu-and rhTRIM5␣s suggested a charge dependence of the restriction by different TRIM5␣s. Taken together, these results suggest that the recognition of the entire capsid surface is a general strategy for TRIM5␣ to restrict MLV but that significantly different specific interactions are involved in the binding of TRIM5␣ from different species to the MLV capsid core. C apsid (CA)-binding retrovirus restriction factors have arisen on at least five occasions in the course of evolution. Their independent evolution is testament to the utility of such factors, either to limit endogenous retrovirus amplification or to inhibit infection by exogenous viruses (1-3). This group of factors includes Fv1 (4, 5), TRIM5␣ (6), and three independently arising hybrid factors, TRIM5CypA1 (7, 8), TRIM5CypA2 (9-12), and TRIM5CypA3 (13) in which a retrotransposed copy of the cellular cyclophilin-A gene has been inserted in the 3= end of the TRIM5 gene. At a minimum, these factors contain a virus CA-binding domain, as well as one or more multimerization domains (14-22).Restriction factor engagement appears to occur soon after retroviral core release into the cell cytoplasm, resulting either in proteasome-mediated CA degradation and an inhibition of reverse transcription (6) or an apparent sequestration of the reverse-transcribed preintegration complex en route to the cell nucleus (23).One of the least-appreciated aspects of restriction by these factors is the ability to restrict multiple species of retrovirus, a property that presumably reflects the ability of these factors to bind several different CA molecules. For example, TRIM5␣ from the cotton-top tamarin can restrict one or more members of the lentivirus, gammaretrovirus, betaretrovirus, and foamy virus genera (24-26), despite extensive differences in the sequences of their CA molecules. Nevertheless, restriction can be sensitive to a single amino acid change, as best characterized by the single change at CA position 110 of murine leukemia virus (MLV) that distinguishes between...

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Section: Discussionsupporting

confidence: 83%

A Comparison of Murine Leukemia Viruses That Escape from Human and Rhesus Macaque TRIM5αs

Ohkura¹,

Stoye²

2013

J Virol

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“…4A and Fig. S4), including the β1/β2 hairpin, L5/6, and L4/5 regions in HIV CA and the corresponding sites on MLV CA (30,33,(45)(46)(47)(48)(49)(50). Specifically, TRIM5α V1 may interact with CA β1/β2 at the center of the CA hexamer, as swapping the V1 region of rhTRIM5α and huTRIM5α resulted in a change of the restriction specificity toward MLV CA with mutations in the β1/β2 region (30).…”

Section: Discussionmentioning

confidence: 99%

“…S5) (17, 18). The most likely scenario is that an extended V1 latches onto the binding surface on one CA molecule, as it has been implicated in interaction with β1/β2 (30) and residue 110 of MLV CA (corresponding to the L5/6 region in HIV CA) (47), whereas V2 and V3 interact with CA molecules in a neighboring hexamer (Fig. 4 D and E).…”

Section: Discussionmentioning

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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“…We also constructed another two strains (designated 86M116E and 86E116E) encoding distinct substitutions at V86. A previous study had shown that V86M CA allows HIV-1 to grow in HeLa-CD4 cells expressing Rh TRIM5a (Pacheco et al, 2010); separate work revealed that the V86E mutant exhibits decreased sensitivity to restriction by the Rh TRIM5a (Soll et al, 2013). When we compared the growth of all three V86 mutants in the presence of CM TRIM5a, 86A116E grew to higher titres in the presence of CM TRIM5a than 86E116E (Fig.…”

Section: Ipmentioning

confidence: 83%

Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis

Sultana

Nakayama

Tobita

et al. 2016

Journal of General Virology

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Old World monkey TRIM5a strongly suppresses human immunodeficiency virus type 1 (HIV-1) replication. A fusion protein comprising cynomolgus macaque (CM) TRIM5 and cyclophilin A (CM TRIMCyp) also potently suppresses HIV-1 replication. However, CM TRIMCyp fails to suppress a mutant HIV-1 that encodes a mutant capsid protein containing a SIVmac239-derived loop between a-helices 4 and 5 (L4/5). There are seven amino acid differences between L4/5 of HIV-1 and SIVmac239. Here, we investigated the minimum numbers of amino acid substitutions that would allow HIV-1 to evade CM TRIMCypmediated suppression. We performed random PCR mutagenesis to construct a library of HIV-1 variants containing mutations in L4/5, and then we recovered replication-competent viruses from CD4 + MT4 cells that expressed high levels of CM TRIMCyp. CM TRIMCyp-resistant viruses were obtained after three rounds of selection in MT4 cells expressing CM TRIMCyp and these were found to contain four amino acid substitutions (H87R, A88G, P90D and P93A) in L4/5. We then confirmed that these substitutions were sufficient to confer CM TRIMCyp resistance to HIV-1. In a separate experiment using a similar method, we obtained novel CM TRIM5a-resistant HIV-1 strains after six rounds of selection and rescue. Analysis of these mutants revealed that V86A and G116E mutations in the capsid region conferred partial resistance to CM TRIM5a without substantial fitness cost when propagated in MT4 cells expressing CM TRIM5a. These results confirmed and further extended the previous notion that CM TRIMCyp and CM TRIM5a recognize the HIV-1 capsid in different manners.

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Adaptation of HIV-1 to cells expressing rhesus monkey TRIM5α

Cited by 33 publications

References 66 publications

A Comparison of Murine Leukemia Viruses That Escape from Human and Rhesus Macaque TRIM5αs

A Comparison of Murine Leukemia Viruses That Escape from Human and Rhesus Macaque TRIM5αs

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis

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