Abstract
HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following membrane fusion, the viral capsid (CA) lattice, which forms the outer face of the retroviral core, makes numerous interactions with cellular proteins that orchestrate the progress of HIV-1 through the replication cycle. The ability of CA to interact with nuclear pore proteins and other host factors around the nuclear pore determines whether nuclear entry occurs. Uncoating, the process by which the CA lattice opens and/or disassembles, is another critical step that must occur prior to integration. Both early and delayed uncoating have detrimental effects on viral infectivity. How uncoating relates to nuclear entry is currently hotly debated. Recent technological advances have led to intense discussions about the timing, location, and requirements for uncoating and have prompted the field to consider alternative uncoating scenarios that presently focus on uncoating at the nuclear pore and within the nuclear compartment. This review describes recent advances in the study of HIV-1 nuclear entry, outlines the interactions of the retroviral CA protein, and discusses the challenges of investigating HIV-1 uncoating.
Highlights
The retroviral capsid (CA) protein is critical for successful progression of the virion through the early post-entry stages of replication, which include the processes that occur between host cell entry and integration
Zila et al used correlative electron microscopy (CLEM) and cryo-electron tomography to analyse the diameter of the central channel of NPCs in SupT1-R5 cells infected with HIV-1 and found that it was ~64 nm in width, which would make it geometrically possible for an intact core to pass through the pore [36] (Figure 1B)
CA-mediated interactions with the host cell cytoskeleton may contribute to docking of cores at the NPC, with the actin cytoskeleton implicated in perinuclear movement of subviral complexes [79], KIF5B required for nucleoporin 358 (Nup358) relocalisation to the cytoplasm [81], and the recent observation of HIV-1 cores observed associated to microtubules around the NPC [36]
Summary
The retroviral capsid (CA) protein is critical for successful progression of the virion through the early post-entry stages of replication, which include the processes that occur between host cell entry and integration. Viruses 2021, 13, 1425 found to influence the conformation of NPCs under certain circumstances [53,54], indicating that the pores may be more flexible than originally thought With this in mind, Zila et al used correlative electron microscopy (CLEM) and cryo-electron tomography (cryo-ET) to analyse the diameter of the central channel of NPCs in SupT1-R5 cells infected with HIV-1 and found that it was ~64 nm in width, which would make it geometrically possible for an intact core to pass through the pore [36] (Figure 1B). In a more recent publication from the same lab, the authors used WT HIV-1 and detected conical and elongated structures that appeared to be open viral cores inside the nucleus of HeLa derived cells [55]
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