About one million people worldwide become infected with HIV, the virus that causes AIDS, each year. To replicate and spread infection, the virus must traffic its genetic material into the cell’s nucleus and integrate it into a chromosome. Research teams led by Dirk Görlich of the Max Planck Institute for Multidisciplinary Science and Thomas Schwartz of the Massachusetts Institute of Technology (MIT) have now discovered that its capsid has evolved into a molecular transporter. As such, it can directly breach an important barrier, which normally protects the cell nucleus against viral invaders. This method of trafficking keeps the viral genome invisible to anti-viral sensors in the cytoplasm.
Forty years after the human immunodeficiency virus (HIV) was discovered to cause AIDS, we have therapies that effectively control the pathogen, but still no cure. The virus infects certain immune cells and hijacks their genetic program to multiply and replicate its own genetic material. Infected cells produce the next generation of virus until they are finally destroyed. The immunodeficiency symptoms of AIDS result from the widespread loss of immune cells that normally fight viruses and other pathogens.
In order to utilize the resources of the host cell, HIV must traffic its genetic material through the cellular defense line into the cell’s nucleus. The nucleus, however, is closely guarded. Its nuclear envelope prevents unwanted proteins or harmful viruses from entering the nucleus and macromolecules from uncontrolled escape. Nevertheless, selected proteins can pass because the barrier is not hermetically sealed.
Thousands of tiny nuclear pores in the nuclear envelope provide a pathway. They control these transport processes with the help of importers and exporters – molecular transporters that capture cargo with valid molecular “passcodes” and deliver them through nuclear pore channels. A ‘smart’ component turns these pores into nature’s most efficient sorting and transport machines.
Picking “Smart” in Nuclear Holes
This “smart” material, called the FG phase, is jelly-like and impermeable to most macromolecules. It fills and blocks the nuclear pore channel. Imports and exports, however, can pass through because their surfaces are optimized to slide through an FG phase.
Cell boundary regulation in the FG phase is extremely rapid—within milliseconds. Likewise, its transport capacity is enormous: a single nuclear pore can move 1,000 transporters per second through its channel. Even at such a high traffic density, the barrier of nuclear pores remains intact and suppresses unwanted border crossings. HIV, however, disrupts this control.
Trafficked genetic material
“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 while crossing the nuclear pore. But there is a size problem,” explains MIT’s Thomas Schwartz. The central pore channel is 40 to 60 nanometers wide. The capsid is about 60 nanometers wide and can only be squeezed through pores. However, a typical cellular cargo will still be covered by a transporter layer that adds at least another ten nanometers. The HIV capsid would then be 70 nanometers wide—too large for the nuclear pore.
Nevertheless, cryo-electron tomography has shown that the HIV capsid enters the nuclear pore. “But how this happens has been a mystery in HIV infection until now.”
Directed by Dirk Gorlich, Max Planck
Masquerading as a molecular transporter
Together with Schwartz, he has now discovered how the virus overcomes its size problem, i.e. by a sophisticated molecular adaptation. “The HIV capsid has evolved into a transporter with an importin-like surface. Thus, it can slide through the FG phase of the nuclear pore. The HIV capsid can thus enter the nuclear pore without the aid of transporters and bypass the defense mechanism that would otherwise allow the virus to invade the cell nucleus. inhibits,” explains the biochemist.
His team succeeded in reproducing FG phases in the laboratory. “Under the microscope, FG phases appear as micrometer-sized spheres that completely exclude normal proteins, but virtually absorb the HIV capsid with its bound contents,” reports Liran Fu, one of the first authors of the study now published in the journal. the nature. “Similarly, the capsid is sucked into the nuclear pore channel. This happens even after all cellular transporters have been removed.”
In one respect the HIV capsid differs fundamentally from previously studied transporters that pass the nuclear pore: it completely encapsulates its cargo and thus conceals its genomic payload from anti-viral sensors in the cytoplasm. Using this strategy, viral genetic material can be trafficked through the cellular virus defense system without being recognized and destroyed. “This makes it another class of molecular transporter besides import and export,” Gorlich emphasized.
There are still many unanswered questions, such as where and how the capsid dissociates to release its contents. However, the observation that the capsid is an importin-like transporter may one day be exploited for better AIDS therapy.
Fu, L., etc. (2024). The HIV-1 capsid enters the FG phase of the nuclear pore like a transport receptor. the nature. doi.org/10.1038/s41586-023-06966-w.