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Early HIV-1 replication requires fusion of viral and cellular membranes that release a fullerene-shaped viral core structure, formed by a lattice of primarily hexameric capsid (CA) rings, into the cellular cytoplasm. The core contains positive-polarity single-strand viral genomic RNA and enzymes that synthesize viral double-strand DNA that is integrated into a host chromosome. Only HIV-1 that release intact cores into the cytoplasm are infectious [1], and disassembly of the core occurs by a regulated process called uncoating. For the purpose of this article, we define uncoating as any dissociation of CA from the viral core. However, the precise mechanism, timing, and location of uncoating is contentious. Recent live-cell single-particle tracking of infectious HIV-1 cores has provided unprecedented insight into uncoating kinetics [2]. One such study found that core integrity, measured by “leakiness” of a core-trapped fluorescent marker, was lost in the cytoplasm approximately 30 min after fusion (after first-strand transfer of reverse transcription) and that this was required for productive infection [3]. However, any such loss of core integrity must not allow innate cellular sensors, such as cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS), to identify and restrict retroviral DNA in the cytoplasm [4]. Another recent study found that a small amount of CA dissociates gradually from the core post-entry before the remaining core structure docks at the nuclear pore complex (NPC), leading to accelerated CA loss, nuclear entry, integration of viral DNA into host DNA, and productive infection [5]. As these two studies measure different events and are not mutually exclusive, it is our view, consistent with that expressed in the review by Francis and Melikyan [2], that HIV-1 uncoating may begin by the loss of core integrity and gradual CA dissociation in the cytoplasm, followed by CA-dependent nuclear docking and accelerated CA loss at the NPC. An alternative model of uncoating is that an intact core arrives at the NPC before uncoating [1]. Here, we discuss the host cell factors subverted by HIV-1 to regulate ordered uncoating in cells (Fig 1), with the caveat that the spatiotemporal specifics of where and when host factors interact with the core and affect CA uncoating requires further investigation.       Open in a separate window   Fig 1  Host cell factors regulate HIV-1 uncoating. The HIV-1 virion, which contains the CypA, ERK2, and eEF1A host proteins that regulate uncoating, binds and fuses with the host cell membrane, and the core is released into the cytoplasm. PDZD8 and CypA binds CA to stabilize cores to promote infection; however, infection is inhibited if CypA associates with MxB, in which MxB oligomers bind CA to hyperstabilize cores. Cellular eEF1A interacts with HIV-1 RT and facilitates uncoating. Dia1 and Dia2 bind CA–NC complexes to facilitate uncoating likely by localized microtubules stabilization. Dynein interacts with the core via the BICD2 adapter protein or direct interaction with IN, and kinesin-1 interacts with the core via the FEZ1 (phosphorylated by MARK2) adapter protein. This is important for transport of the replication complexes through the cytoplasm to MTOCs at the nuclear periphery as well as uncoating. Pin1 binds CA phosphorylated by MEK1/2 activated ERK2 during virion maturation to facilitate uncoating. MELK also phosphorylates CA to promote uncoating. HIV-1 RT binds eEF1A to stabilize the RTC. The NPC proteins Nup358 and Nup153 help import the PIC, and Nup358 is relocalized to the cytoplasm by KIF5B, while Nup153 prolongs CA association with PICs in the nucleus. TNPO3 localizes CPSF6 to the nucleus to prevent CPSF6-dependent hyperstable cores, and TNPO3 may also help complete CA dissociation from replication complexes in the nucleus. This figure does not attempt to illustrate the spatiotemporal specifics of where and when host factors interact with the core and regulate CA uncoating. Green text: promotes uncoating for optimal kinetics. Orange text: delays uncoating for optimal kinetics. Red text: causes hyperstable cores and inhibits infection. Only viral and host proteins relevant in uncoating and discussed in this article are included in the figure. CA, capsid; CPSF6, cleavage and polyadenylation specificity factor 6; CypA, cyclophilin A; BICD2, bicaudal D2; Dia1/2, diaphanous-related formins 1 and 2; eEF1A, eukaryotic translation elongation factor 1A; ERK2, extracellular signal-regulated kinase 2; FEZ1, fasciculation and elongation factor zeta 1; IN, integrase; KIF5B, kinesin-1 heavy chain; NC, nucleocapsid; NPC, nuclear pore complex; Nup, nucleoporin; MARK2, microtubule affinity-regulating kinase 2; MEK1/2, mitogen-activated protein 1 and 2; MELK, maternal embryonic leucine zipper kinase; MTOC, microtubule-organizing centers; MxB, myxovirus resistance protein B; PDZD8, PDZ domain-containing 8 protein; PIC, pre-integration complex; RT, reverse transcriptase; RTC, reverse transcription complexes; TNPO3, transportin 3.

Toward the “unravelling” of HIV: Host cell factors involved in HIV-1 core uncoating