HIV entry mechanism into immune cell nucleus revealed

  In cells that have no KIF5B or Nup358, the researchers note that HIV-1 entry is much reduced, and the virus (red) accumulates around the outside of the cell nucleus (blue).
Image credit: Loyola University Chicago

 

Written by Catharine Paddock PhD

Published: Thursday 23 June 2016

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Once HIV enters an immune cell, it has to make its way into the nucleus to fuse with the cell's DNA. Most viruses wait until the cell divides to do this, but HIV is too impatient. Instead, the virus hijacks a protein and makes it enlarge pores in the membrane surrounding the nucleus that the cell uses to pass materials to and from the nucleus.

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This was the main finding of new research published in the journal PLOS Pathogens by a team from Loyola University, Chicago, IL.
Senior author Edward M. Campbell, associate professor in the Department of Microbiology and Immunology at Loyola's Stritch School of Medicine, says the discovery could lead to new drugs to treat HIV/AIDS.
Viruses cause disease by invading cells and changing how they behave. Different viruses target different cells. HIV targets cells in the immune system.
As HIV impairs and destroys infected people's immune cells, their defense against disease and infection weakens. The most advanced stage of infection - which can take from 2-15 years to develop - is called AIDS.
According to the World Health Organization (WHO), there are around 37 million people living with HIV worldwide, and around 2 million become newly infected every year.
HIV-1 is the predominant strain of HIV that causes the vast majority of HIV infections worldwide. When people talk about HIV, they usually mean HIV-1.
Without host cells, viruses cannot sustain themselves and reproduce. They have no energy source or metabolic engine of their own; they have to enter the host cell, penetrate its nucleus, and fuse with its DNA to take control of cell machinery to make their own proteins and replicate.

HIV-1 hijacks cell protein to enlarge nuclear pores

Most viruses take the opportunity to enter the nucleus when the host cell divides and the nuclear membrane or envelope - the wall that protects the nucleus and its precious cargo of DNA - breaks down. But HIV-1 does not wait for this; somehow, it manages to enter the nucleus of non-dividing cells. Exactly how it does this has been a mystery for years.
What has been especially baffling is that the HIV-1 capsid - the protein shell that protects the genetic material of the virus - is some 50 percent larger than the pores in the nuclear envelope. These pores normally allow proteins and other materials in the host cell to travel to and from between the nucleus and the cell body.
The discovery that Prof. Campbell and colleagues make in their study surrounds a protein called KIF5B that normally transports various materials inside the cell away from the nucleus.
They found that HIV-1 hijacks KIF5B and induces it to tear off pieces of the nuclear envelope and transport them away from the nucleus, causing the pores to become big enough to allow HIV-1 to pass through. The pieces that are torn off are proteins called Nup358.
In cells that have no KIF5B or Nup358, the authors note that HIV-1 entry is much reduced, and the virus accumulates around the outside of the nuclear envelope.

Discovery could lead to new drug for HIV

The team suggests the finding could lead to a new type of anti-HIV drug that stops KIF5B from disrupting the pores in the nuclear envelopes of host cells.
Such a drug might slow HIV's entry into the host cell nucleus long enough to give the immune system time to raise the alarm and destroy the virus.
Cells have natural mechanisms for detecting viruses in their cytoplasm - the fluid that fills the cell and surrounds the nucleus. But HIV-1 is able to enter the nucleus before these mechanisms have time to react.
Drugs that disable the hijacking of KIF5B would trap HIV-1 in the cytoplasm. This would not only prevent infection, but also increase the chance of HIV-1 being detected and eliminated.

"It's like making a bank vault harder to break into. In addition to making the money more secure, it would increase the chance of sounding the alarm and catching the burglars."

Prof. Edward M. Campbell

Discover how a new antibody treatment may offer a long-term solution for the control of HIV.

Written by Catharine Paddock PhD

 

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