In order for HIV to replicate, the viral genome must enter into the cell nucleus and integrate into the host cell chromosome. Previous work suggests that the entry proceeds through nuclear pore complexes (NPCs). Now, researchers have uncovered that the viral capsid has evolved into a molecular transporter that can cross the permeability barrier of the NPC. This mechanism keeps the viral genome invisible to anti-viral sensors in the cytoplasm.

This work is published in Nature in the paper, “HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor.

The nucleus of the cell is closely guarded. Its nuclear envelope prevents unwanted proteins or harmful viruses from entering the nucleus. Thousands of nuclear pores in the nuclear envelope control the transport processes with the help of importins and exportins—molecular transporters that deliver cargo through the nuclear pore channel. A single nuclear pore can transfer up to 1,000 transporters per second through its channel.

“HIV packages its genome into a capsid. Recent evidence suggests that the genome stays inside the capsid until it reaches the nucleus, and thus also when passing the nuclear pore. But there is a size problem,” said Thomas Schwartz, PhD, professor of biology at MIT.

The central pore channel is 40 to 60 nanometers wide. The capsid has a width of about 60 nanometers and could just squeeze through the pore. However, a normal cellular cargo would still be covered by a transporter layer that adds at least another ten nanometers. The HIV capsid would then be 70 nanometers wide—too big for a nuclear pore.

“Nevertheless, cryo-electron tomography has shown that the HIV capsid gets into the nuclear pore. But how this happens has been so far a mystery in HIV infection,” said Dirk Görlich, PhD, director and scientific member of the Max Planck Institute for Multidisciplinary Sciences.

The permeability barrier of the NPC can be described as an FG phase that “is assembled from cohesively interacting phenylalanine–glycine (FG) repeats and is selectively permeable to cargo captured by nuclear transport receptors (NTRs).”

Together with Schwartz, Görlich has now discovered how the virus overcomes its size problem. “The HIV capsid has evolved into a transporter with an importin-like surface,” Görlich explained. “This way, it can slide through the FG phase of the nuclear pore. The HIV capsid can thus enter the nuclear pore without helping transporters and bypass the protective mechanism that otherwise prevents viruses from invading the cell nucleus.”

The authors showed that HIV-1 capsids can target NPCs efficiently—in an NTR-independent manner—and bind directly to several types of FG repeats, including barrier-forming repeats. The capsid partitions into an in vitro assembled cohesive FG phase that can serve as an NPC mimic. Entry of the capsid protein into an FG phase is greatly enhanced by capsid assembly.

The HIV capsid differs fundamentally from previously studied transporters that pass nuclear pores because it encapsulates its cargo completely and thus conceals its genomic payload from anti-viral sensors in the cytoplasm. “This makes it another class of molecular transporters alongside importins and exportins,” Görlich emphasized.

Unanswered questions remain, such as where and how the capsid disintegrates to release its contents. However, the observation that the capsid is an importin-like transporter might one day be exploited for better AIDS therapies.

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