How HIV Kills Bystander Cells

28 November 2010

Interview with

Professor Warner Greene, University of California at San Francisco

Chris -   Wednesday, December the 1st is going to be World Aids Day and 2011 actually marks the 30th anniversary of the discovery of HIV - the agent that causes AIDS.  So it's very timely that this week scientists have announced that they have solved one of the big outstanding questions that surrounds HIV infection, which is why the virus is so damaging to the immune system.  Professor Warner Greene is the Director of the Gladstone Institute of Virology and Immunology at the University of California in San Francisco.  He's with us now.  Warner, hello.  Welcome to the Naked Scientists.  First, can you give us a brief potted history of what actually happens during HIV infection?  In other words, how does the virus get into cells and what's its life cycle?

Warner -   Good evening, Chris.  I'm happy to do that and it's too bad as we're celebrating the 30th World AIDS day that we haven't ended this epidemic but the number of new infections are in fact declining markedly throughout world which is very good news.  In terms of the life cycle of HIV, HIV binds to the cell surface, micro-injects its RNA genome into the cytoplasm of the cell, and then converts that RNA into DNA, a double-stranded version of the DNA, hence, the name retrovirus - reverse flow of genetic information.  The DNA is then integrated into our own chromosomes, the DNA is then expressed into new proteins and RNA which is packaged into new virions which bud from the cell, and starts the entire infection process over again.

Crystallographic structure of the V-set and C2 domains of human CD4Chris -   And the cells that are targeted are white blood cells, CD4, they carry that marker on their surface, T-cells, without which the immune system can't function properly.  So one logical conclusion is the virus infects the very cells that orchestrate the immune response.  So if you damage them then the immune system is harmed.

Warner -   Correct.  But the real question is, how are these CD4 T-cells dying?  It was quite clear that the number of cells productively infected with HIV could not explain.  In other words, direct killing could not explain the massive CD4 T-cell loss that occurs during HIV infection.  Then a theory was advanced that it's not the directly infected cells but cells surrounding the infected cell, bystander cells, that are dying.  Our study now shows for the first time that in fact, it is these bystander cells which are the principal cause of CD4 T-cell loss, but they themselves are becoming infect but in an abortive manner, an incomplete infection that arrests early after the virus begins the reverse transcription process.

Chris -   How did you do this work?  How did you prove that?

Warner -   Well the first key was to use a primary lymphoid tissue.  We used tonsil and in this tissue, we were then able to use each of the different types of new HIV drugs that interfere with precise steps in the viral life cycle.  We were able to interrupt the life cycle with these drugs and ask whether or not, CD4 T-cell killing was blocked or not.

Chris -   Ingenious.  So, by adding a different drug that works on a different aspect of the life cycle, you interrupt at that stage, see if the cell dies.  If it doesn't die, that tells you that the effect that you see, the bystander death, in an infected patient must lie downstream of that blockade.  If the cell does die, it's upstream of where the drug works and that confines a bit of the viral life cycle that must be doing the damage.

Warner -   Right.  We were able to narrow-in the death window - as we called it - to a step during the reverse transcription process, whereby, the DNA is elongated into a chain longer than 150 base pairs.  One of the real surprises in our study was, it's not the virus that's causing the CD4 T-cells to die, but rather, it's the host cell's response to the occurrence or to the accumulation of cytoplasmic DNA in the cell cytoplasm.  That's what triggers a defensive response in the cell.  In an attempt to protect the host, the CD4 T-cell commits suicide.

Chris -   So this is something we've acquired through evolution to defend us against viral attack.  Cells that sense this cytoplasmic DNA, genetic material in the cell where it shouldn't be, tells the cell, "I'm infected with a virus.  I'll kill myself to protect the rest of the body."  Unfortunately, when you've got the scale of infection going on like you have with HIV, this has deleterious effects then.

Warner -   Right and the other twist of the story that was a real surprise was that these cells do not die silently, but rather they are dying a fiery death with the release of what's called pyroptosis which is the release of inflammatory cytokines.  The entire cellular contents of the cell are dumped which increases the inflammatory response. We now know that there is a close relationship between HIV and inflammation, that these two go hand in hand, dictating disease progression.

Chris -   What is the implication of this, just to finish this up?  Does this mean that we're now closer to understanding how to intervene in the viral life cycle better, so people who are infected with HIV don't lose all their immune cells in this way?

Warner -   Well, one of the great milestones in modern medicine is the creation of a panoply of anti-retroviral drugs, 26 FDA approved drugs for HIV therapy at last count.  All of these drugs can interfere with this death pathway.  However, the new link to inflammation, a death with inflammation, now allows us to explore the possibility of removing that inflammatory component which might allow the virus to grow in a non-pathogenic way.  This might be important for certain clinical settings.

Chris -   Let's hope so.  Warner, thank you very much.  That's Warner Greene who is Professor of medicine, microbiology and immunology at the University California, San Francisco.

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