Numerous viruses, including HIV-1, exploit the microtubule network to traffic toward the nucleus during infection. Although numerous studies have observed a role for the minus-end microtubule motor dynein in HIV-1 infection, the mechanism by which the viral core containing the viral genome associates with dynein and induces its perinuclear trafficking has remained unclear. Here, we report that the dynein adapter protein bicaudal D2 (BICD2) is able to interact with HIV-1 viral cores in target cells. We also observe that BICD2 can bind in vitro-assembled capsid tubes through its CC3 domain. We observe that BICD2 facilitates infection by promoting the trafficking of viral cores to the nucleus, thereby promoting nuclear entry of the viral genome and infection. Finally, we observe that depletion of BICD2 in the monocytic cell line THP-1 results in an induction of IFN-stimulated genes in these cells. Collectively, these results identify a microtubule adapter protein critical for trafficking of HIV-1 in the cytoplasm of target cells and evasion of innate sensing mechanisms in macrophages.
The HIV-1 capsid protein makes up the core of the virion and plays a critical role in early steps of HIV replication. Due to its exposure in the cytoplasm after entry, HIV capsid is a target for host cell factors that act directly to block infection such as TRIM5α and MxB. Several host proteins also play a role in facilitating infection, including in the protection of HIV-1 capsid from recognition by host cell restriction factors. Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the wellcharacterized HIV restriction factor TRIM5α. This restriction occurs at the step of reverse transcription, is independent of interferon stimulation, and limits HIV-1 infection in key target cells of HIV infection including CD4+ T cells and monocyte-derived dendritic cells. TRIM34 can also restrict some SIV capsids. TRIM34 restriction requires TRIM5α as knockout or knockdown of TRIM5α results in a loss of antiviral activity. Through immunofluorescence studies, we show that TRIM34 and TRIM5α colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with WT HIV-1 capsids. Our results identify TRIM34 as an HIV-1 CA-targeting restriction factor and highlight the potential role for heteromultimeric TRIM interactions in contributing to restriction of HIV-1 infection in human cells.
1The HIV-1 capsid protein makes up the core of the virion and plays a critical role in early 2 steps of HIV replication. Due to its exposure in the cytoplasm after entry, HIV capsid is a 3 target for host cell factors that act directly to block infection such as TRIM5 and MxB. 4 Several host proteins also play a role in facilitating infection, including in the protection 5 of HIV-1 capsid from recognition by host cell restriction factors. Through an unbiased 6 screening approach, called HIV-CRISPR, we show that the Cyclophilin A-binding 7 deficient P90A HIV-1 capsid mutant becomes highly-sensitized to TRIM5alpha restriction 8 in IFN-treated cells. Further, the CPSF6-binding deficient, N74D HIV-1 capsid mutant is 9 sensitive to restriction mediated by human TRIM34, a close paralog of the well-10 characterized HIV restriction factor TRIM5. This restriction occurs at the step of reverse 11 transcription, is independent of interferon stimulation and limits HIV-1 infection in key 12 target cells of HIV infection including CD4+ T cells and monocyte-derived dendritic cells. 13 TRIM34 restriction requires TRIM5alpha as knockout or knockdown of TRIM5alpha 14 results in a loss of antiviral activity. TRIM34 can also restrict some SIV capsids. Through 15 immunofluorescence studies, we show that TRIM34 and TRIM5alpha colocalize to 16 cytoplasmic bodies and are more frequently observed to be associated with infecting 17 N74D capsids than with WT capsids. Our results identify TRIM34 as an HIV-1 CA-18 targeting restriction factor and highlight the potential role for heteromultimeric TRIM 19 interactions in contributing restriction of HIV-1 infection in human cells.
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