Dynactin 1 negatively regulates HIV-1 infection by sequestering the host cofactor CLIP170

Abstract

Many viruses directly engage and require the dynein–dynactin motor–adaptor complex in order to transport along microtubules (MTs) to the nucleus and initiate infection. HIV type 1 (HIV-1) exploits dynein, the dynein adaptor BICD2, and core dynactin subunits but unlike several other viruses, does not require dynactin-1 (DCTN1). The underlying reason for HIV-1’s variant dynein engagement strategy and independence from DCTN1 remains unknown. Here, we reveal that DCTN1 actually inhibits early HIV-1 infection by interfering with the ability of viral cores to interact with critical host cofactors. Specifically, DCTN1 competes for binding to HIV-1 particles with cytoplasmic linker protein 170 (CLIP170), one of several MT plus-end tracking proteins (+TIPs) that regulate the stability of viral cores after entry into the cell. Outside of its function as a dynactin subunit, DCTN1 also functions as a +TIP that we find sequesters CLIP170 from incoming particles. Deletion of the Zinc knuckle (Zn) domain in CLIP170 that mediates its interactions with several proteins, including DCTN1, increased CLIP170 binding to virus particles but failed to promote infection, further suggesting that DCTN1 blocks a critical proviral function of CLIP170 mediated by its Zn domain. Our findings suggest that the unique manner in which HIV-1 binds and exploits +TIPs to regulate particle stability leaves them vulnerable to the negative effects of DCTN1 on +TIP availability and function, which may in turn have driven HIV-1 to evolve away from DCTN1 in favor of BICD2-based engagement of dynein during early infection.

The host cytoskeleton: a key regulator of early HIV‐1 infection

“…DCTN1 both binds to CLIP170 and competes with it for binding to EB1 [76]. Similar to EB1, due to viral mimicry of EB1's +TIP-binding activity, DCTN1 negatively regulates HIV-1 infection by restricting CLIP170 availability, both through direct competition for binding to the capsid protein EBH-like motif in the MHR of incoming capsids and through sequestration of CLIP170 from viral particles through direct binding to its zinc knuckle domain [77]. Given that these +TIPs and motor adaptors are predominantly localized in the cytoplasm, like several other cellular factors that regulate capsid stability, these findings support the notion that partial uncoating in the cytoplasm is functionally important for early HIV-1 infection.…”

“…BICD2 associates directly with the HIV‐1 capsid in in vitro binding assays, and loss of BICD2 results in almost complete abrogation of microtubule‐based transport of HIV‐1 particles in infected cells [86,87]. By contrast, the dynactin adaptor subunit, DCTN1, is either not required or is in fact inhibitory to infection [77,87]. As discussed above, this is due to its secondary role as a +TIP and its negative effects on CLIP170 availability to HIV‐1 particles.…”