An HIV-1 capsid binding protein TRIM11 accelerates viral uncoating

Abstract

BackgroundSeveral members of the TRIM family have been implicated in antiviral defense. Our previous report showed that human TRIM11 potently inhibited HIV-1 transduction by reducing the viral reverse transcripts. These results prompted us to examine the effect of TRIM11 on HIV-1 uncoating, which is closely related to viral reverse transcription.ResultsUsing a combination of in vitro binding and in situ proximity ligation assay, we showed that TRIM11 could interact with HIV-1 capsid. Overexpression of TRIM11 accelerates HIV-1 uncoating and reduces viral reverse transcription indicated by the fate-of-capsid assay and quantitative PCR respectively. Knockdown of TRIM11 enhanced HIV-1 capsid stability and increased viral reverse transcription. However, the replication of another retrovirus MLV is not affected by TRIM11. Moreover, the reverse transcription of HIV-1 mutant bearing capsid G89V showed insensitivity to restriction by TRIM11, indicating that the viral determinant of restriction by TRIM11 might reside on capsid. Using microtubule dynamics inhibitors, we revealed that microtubule dynamics contributes to TRIM11-mediated HIV-1 capsid premature disassembly and the reduction of reverse transcription levels. Finally, we demonstrated that TRIM11 inhibits HIV-1 transduction and accelerates viral uncoating in HIV-1 permissive THP-1-derived macrophages.ConclusionsWe identify TRIM11 as a new HIV-1 capsid binding protein. Our data also reveal that TRIM11 restricts HIV-1 reverse transcription by accelerating viral uncoating, and microtubule dynamics is implicated in TRIM11-imposed block to early events of HIV-1 replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0306-5) contains supplementary material, which is available to authorized users.

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…Mobilization of the host cell's cytoskeletal components to limit viral invasion has been described for TRIMs [57,58]. TRIM11 was identified as an HIV-1 binding protein that recognizes the viral capsid, leading to early uncoating and restriction of reverse transcription [57].…”

“…Mobilization of the host cell's cytoskeletal components to limit viral invasion has been described for TRIMs [57,58]. TRIM11 was identified as an HIV-1 binding protein that recognizes the viral capsid, leading to early uncoating and restriction of reverse transcription [57]. This antiviral function was linked to the host microtubule system and not to other more common degradation pathways involving proteasomes or lysosomes [57].…”

The TRIMendous Role of TRIMs in Virus–Host Interactions

“…A plethora of TRIM-mediated restriction mechanisms targeting HIV-1 and other retroviruses have been proposed [ 15 ], and have been reviewed previously [ 6 ]. More recent reports acknowledged TRIM11 as a potent host restriction factor of HIV-1 [ 114 , 190 ]. The mechanisms of TRIM11-mediated restriction include curbing the amount of viral reverse transcription products allowed to accumulate in the host.…”

“…Through an interaction with the viral capsid-nucleocapsid protein (CA-NC) complexes, TRIM11 promotes premature uncoating and release of the viral genetic material, reducing transduction efficiency. Neither proteasomal nor lysosomal inhibitor treatments recovered viral p24 protein in the pellets of TRIM11 overexpressing cells, suggesting that ubiquitin-mediated degradation by the proteasome or lysosomal acidification is not required for TRIM11-mediated uncoating [ 190 ]. Furthermore, while rhTRIM5α-mediated inhibition of HIV-1 is rescued by proteasome inhibitors [ 170 , 171 ], TRIM11-mediated inhibition was not, indicating that TRIM11 and TRIM5α restrict HIV-1 by different mechanisms [ 114 , 190 ].…”

“…Neither proteasomal nor lysosomal inhibitor treatments recovered viral p24 protein in the pellets of TRIM11 overexpressing cells, suggesting that ubiquitin-mediated degradation by the proteasome or lysosomal acidification is not required for TRIM11-mediated uncoating [ 190 ]. Furthermore, while rhTRIM5α-mediated inhibition of HIV-1 is rescued by proteasome inhibitors [ 170 , 171 ], TRIM11-mediated inhibition was not, indicating that TRIM11 and TRIM5α restrict HIV-1 by different mechanisms [ 114 , 190 ]. In contrast, using the microtubule dynamics inhibitors nocodazole and taxol, the authors were able to demonstrate a restoration of HIV-1 capsid levels in cells supplemented with exogenous TRIM11, suggesting that microtubules may contribute to TRIM11-mediated HIV-1 restriction [ 190 ].…”