Home Medizin Es wurde festgestellt, dass das HIV-Virus eine verborgene Transportfähigkeit besitzt

Es wurde festgestellt, dass das HIV-Virus eine verborgene Transportfähigkeit besitzt

von NFI Redaktion

Approximately one million people worldwide are infected with HIV, the virus that causes AIDS, every year. To replicate and spread the infection, the virus must shuttle its genetic material into the cell nucleus and integrate it into a chromosome. Research teams led by Dirk Görlich from the Max Planck Institute for Multidisciplinary Science and Thomas Schwartz from the Massachusetts Institute of Technology (MIT) have discovered that its capsid has evolved into a molecular transporter, allowing it to directly breach a crucial barrier that normally protects the cell nucleus from viral invaders. Through this form of smuggling, the viral genome remains invisible to antiviral sensors in the cytoplasm.

Four decades after the discovery of the Human Immunodeficiency Virus (HIV) as the cause of AIDS, there are treatments that effectively control the pathogen, but a cure still does not exist. The virus infects specific immune cells and hijacks their genetic program to replicate and multiply its own genetic material. The infected cells then produce the next generation of viruses until they are eventually destroyed. The immune deficiency symptoms of AIDS result from the massive loss of immune cells that typically fight viruses and other pathogens.

To use the host cell’s resources, HIV must shuttle its genetic material through cellular defense lines into the cell nucleus. However, the nucleus is strictly guarded, and its nuclear envelope prevents unwanted proteins or harmful viruses from entering the nucleus, while also preventing macromolecules from escaping uncontrollably. However, selected proteins can pass through, as the barrier is not hermetically sealed.

Thousands of tiny nuclear pores in the nuclear envelope serve as a passage. They control these transport processes with the help of importins and exportins – molecular transporters that capture loads with valid molecular „passcodes“ and transport them through the nuclear pore channel. An „intelligent“ material turns these pores into one of nature’s most efficient sorting and transportation machines.

„Smart“ Sorting in the Nuclear Pore

This „intelligent“ material, called the FG-phase, is gel-like and impenetrable for most macromolecules. It fills and blocks the nuclear pore channel. Importins and exportins, however, can pass through, as their surfaces are optimized for sliding through an FG-phase.

The cell’s border control in the FG-phase is extremely fast – within milliseconds. Its transport capacity is enormous as well: a single nuclear pore can transport up to 1,000 transporters per second through its channel. Even with such high traffic density, the barrier of the nuclear pores remains intact and continues to suppress unwanted border crossings. However, HIV undermines this control.

Smuggled Genetic Material

„HIV packages its genome into a capsid. Current findings suggest that the genome remains in the capsid until it reaches the cell nucleus, thus also when passing the nuclear pore. However, there is a size problem,“ explains Thomas Schwartz from 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 load 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 large for a nuclear pore.

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


Dirk Görlich, Max Planck Director

Disguised as a Molecular Transporter

Along with Schwartz, Görlich has now discovered how the virus overcomes its size problem through a sophisticated molecular adaptation. „The HIV capsid has evolved into a transporter with an importin-like surface. This way, it can slide through the FG-phase of the nuclear pore. The HIV capsid can thus penetrate the nuclear pore without aiding the transporters as usual and bypass the normal protective mechanism that prevents viruses from entering the cell nucleus,“ explained the biochemist.

Their team has successfully reproduced FG-phases in the laboratory. „Under the microscope, FG-phases appear as micrometer-sized beads that completely exclude normal proteins but effectively engulf the HIV capsid with its enclosed content,“ reported Liran Fu, one of the lead authors of the study published in the journal Nature. „In a similar manner, the capsid is suctioned into the nuclear pore channel. This happens even when all cellular transporters have been removed.“

In a fundamental aspect, the HIV capsid differs from previously studied transporters that pass through nuclear pores: it completely encases its load, effectively hiding its genomic payload from antiviral sensors in the cytoplasm. With this trick, the viral genetic material can be smuggled through the cellular virus defense system unnoticed and destroyed. „In addition to importins and exportins, it is another class of molecular transporter,“ emphasized Görlich.

There are still many open questions, such as where and how the capsid disassembles and releases its content. However, the observation that the capsid is an importin-like transporter could one day be used for better AIDS therapies.

Source:

Max Planck Institute for Multidisciplinary Science

Journal reference:

Fu, L., et al. (2024). HIV-1 Capsids Enter the FG-Phase of Nuclear Pores Like a Transport Receptor. Nature. doi.org/10.1038/s41586-023-06966-w.

Related Posts

Adblock Detected

Please support us by disabling your AdBlocker extension from your browsers for our website.