Revealed: HIV's Trick For Invading The Nucleus of a Host's Cell

Good news! Amazing stuff! Unraveling the secrets of viral infection one step at a time!

"Scientists have made an important discovery in understanding how the Human Immunodeficiency Virus – better known as HIV – breaks into the nucleus of a cell, enabling it to replicate and spread.

This process has been something of a mystery until now, and the research team ...  says that their findings will help in understanding HIV and its impact on the body. Ultimately, it could lead to better treatments. ..."

"... According to their models, the HIV capsid, which is cone-shaped, points its smaller end into the pores of the nucleus and then ratchets itself in. Once the pore is open enough, the capsid is elastic enough to squeeze through. Importantly, the scientists said, both the structural flexibility of the capsid and the pore itself play a role in the infiltration process. ...

The study also provides the most extensive simulation yet of the nuclear pore itself, which is important in many biological processes. ...
built a painstaking computer simulation of both the HIV capsid and the nuclear pore complex—accounting for thousands of proteins working together. ...
They also found both the pore and the capsid deform as it goes. Interestingly, the lattice of molecules that make up the capsid structure develops little regions of less order to accommodate the stress of the pressure. ..."

From the significance and abstract:
"Significance

Nuclear pore complexes form a gate that mediates the transport of cargo between the cytoplasm and nucleus. Here, we investigate the factors regulating the nuclear entry of intact HIV-1 capsid using coarse-grained simulations and structural analysis. The central channel dynamically expands to allow capsid passage, demonstrating the pleomorphic nature of the channel necessary for transporting large cargoes. Stress induced by the central channel confinement and uncondensed internal genomic material generates correlated striated patterns of lattice disorder across the capsid surface, which are a measure of its “elasticity.” Our study demonstrates that modulating the capsid lattice elasticity can be an effective strategy for the development of antiviral drugs to prevent viral nuclear import and impair infection.

Abstract

Nuclear import and uncoating of the viral capsid are critical steps in the HIV-1 life cycle that serve to transport and release genomic material into the nucleus. Viral core import involves translocating the HIV-1 capsid at the nuclear pore complex (NPC). Notably, the central channel of the NPC appears to often accommodate and allow passage of intact HIV-1 capsid, though mechanistic details of the process remain to be fully understood. Here, we investigate the molecular interactions that operate in concert between the HIV-1 capsid and the NPC that regulate capsid translocation through the central channel. To this end, we develop a “bottom-up” coarse-grained (CG) model of the human NPC from recently released cryo-electron tomography structure and then construct composite membrane-embedded CG NPC models. We find that successful translocation from the cytoplasmic side to the NPC central channel is contingent on the compatibility of the capsid morphology and channel dimension and the proper orientation of the capsid approach to the channel from the cytoplasmic side. The translocation dynamics is driven by maximizing the contacts between phenylalanine-glycine nucleoporins at the central channel and the capsid. For the docked intact capsids, structural analysis reveals correlated striated patterns of lattice disorder likely related to the intrinsic capsid elasticity. Uncondensed genomic material inside the docked capsid augments the overall lattice disorder of the capsid. Our results suggest that the intrinsic “elasticity” can also aid the capsid to adapt to the stress and remain structurally intact during translocation."

Revealed: HIV's Trick For Invading The Nucleus of a Host's Cell : ScienceAlert: Scientists have made an important discovery in understanding how the Human Immunodeficiency Virus – better known as HIV – breaks into the nucleus of a cell, enabling it to replicate and spread.

Simulations show how HIV sneaks into the nucleus of the cell UChicago chemists assemble massive model of the nuclear pore complex and HIV-1 virus capsid

HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex (open access)

A simulation of the pore of the nucleus of the cell. From left, an overhead view; center, a cutaway view; and at right, with an HIV capsid (shown in blue-green) embedded.

Fig. 1 Overview of the CG molecular model of the CR, NR, and IR.