HIV has been found to have a latent transport capacity

About one million people worldwide become infected with HIV, the virus that causes AIDS, each year. To reproduce and spread infection, the virus must smuggle its genetic material into the cell’s nucleus and integrate it into a chromosome. Research teams led by Dirk Görlich at the Max Planck Institute for Multidisciplinary Science and Thomas Schwartz at the Massachusetts Institute of Technology (MIT) have now discovered that its capsid has evolved into a molecular transporter. Therefore, it can directly breach a critical barrier, which normally protects the cell nucleus from viral invaders. This mode of trafficking keeps the viral genome invisible to antiviral sensors in the cytoplasm.

Forty years after the discovery of the human immunodeficiency virus (HIV) as the cause of AIDS, we have treatments that effectively keep the pathogen under control, but there is still no cure. The virus infects certain cells of the immune system and tampers with their genetic program in order to multiply and reproduce its own genetic material. The infected cells then produce the next generation of viruses until they are finally destroyed. The immunodeficiency symptoms of AIDS result from the massive loss of immune cells that normally fight viruses and other pathogens.

To use the host cell’s resources, HIV must smuggle its genetic material through cellular defense lines into the cell nucleus. The core, however, is closely guarded. Its nuclear envelope prevents unwanted proteins or harmful viruses from entering the nucleus and macromolecules from an uncontrolled escape. However, selected proteins can pass because the barrier is not hermetically sealed.

Thousands of tiny nuclear pores in the nuclear envelope provide a passageway. They control these transport processes with the help of imports and exports – molecular transporters that pick up cargoes with valid molecular “passwords” and deliver them through the nuclear resource channel. A “smart” material turns these resources into one of nature’s most efficient sorting and transport machines.

“Smart” screening of the nuclear resource

This “smart” material, called the FG phase, is jelly-like and impermeable to most macromolecules. It fills and clogs the nuclear pore canal. Imports and exports, however, can pass because their surfaces are optimized for sliding through an FG phase.

Cell boundary control in the FG phase occurs extremely rapidly – ​​within milliseconds. Similarly, its transport capacity is enormous: a single nuclear resource can transport up to 1,000 carriers per second through its channel. Even with such high traffic density, the nuclear resource barrier remains intact and continues to suppress unwanted border crossings. HIV, however, subverts this control.

Contraband genetic material

“HIV packages its genome in a capsid. Recent evidence shows that the genome remains inside the capsid until it reaches the nucleus, and therefore also when it passes through 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 could just squeeze through the pore. However, a normal cellular load would still be covered by a carrier layer that adds at least another ten nanometers. The HIV capsid would then be 70 nanometers across – too large for a nuclear pore.

However, cryo-electron tomography showed that the HIV capsid enters the nuclear pore. But how this happens has so far been a mystery in HIV infection.”

Dirk Görlich, Max Planck Director

Camouflage as a molecular transporter

Together with Schwartz, he has now discovered how the virus overcomes its size problem, namely with a sophisticated molecular adaptation. “The HIV capsid has evolved into a transporter with an immortin-like surface. In this way, it can slip through the FG phase of the nuclear pore. The HIV capsid can thus enter the nuclear pore without the help of transporters and to bypass the protective mechanism that otherwise prevents viruses from invading the cell nucleus,” explains the biochemist.

His team succeeded in reproducing FG phases in the laboratory. “Under the microscope, the FG phases appear as micrometer-sized spheres that completely exclude normal proteins, but essentially absorb the HIV capsid with its contents,” reports Liran Fu, one of the first authors of the study now published in the journal. Nature. “Similarly, the capsid is taken up into the nuclear pore channel. This happens even after all cellular transporters are removed.”

In one respect, the HIV capsid differs fundamentally from previously studied nuclear pore-passing transporters: it completely encapsulates its cargo and thus hides its genomic cargo from antiviral sensors in the cytoplasm. Using this trick, viral genetic material can be smuggled through the cell’s virus defense system without being recognized and destroyed. “This makes it another class of molecular transporters along with importins and exportins,” Görlich points out.

There are still many unanswered questions, such as where and how the capsid disintegrates to release its contents. However, the observation that the capsid is an importin-like transporter may one day be exploited for better AIDS treatments.