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Brian Krueger, PhD
Columbia University Medical Center
New York NY USA

Brian Krueger is the owner, creator and coder of LabSpaces by night and Next Generation Sequencer by day. He is currently the Director of Genomic Analysis and Technical Operations for the Institute for Genomic Medicine at Columbia University Medical Center. In his blog you will find articles about technology, molecular biology, and editorial comments on the current state of science on the internet.

My posts are presented as opinion and commentary and do not represent the views of LabSpaces Productions, LLC, my employer, or my educational institution.

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Wednesday, December 15, 2010

Yesterday there was some buzz over at Huffington Post about a stem cell cure for HIV.  I first ran across the article via a link a friend of mine had posted on Facebook.   The HuffPo piece is scant on details, so I’ll provide a quick run down on what’s going on here. But first, a lesson in HIV virology…


HIV Virion Credit: NIH

Human immunodeficiency virus (HIV) was first discovered in the 1980’s when gay men and IV drug users started turning up in hospitals with very odd opportunistic infections like Kaposi’s Sarcoma Herpes virus.  These individuals had severely compromised immune systems and the original name given to the condition was gay related immunodeficiency disorder (GRID).  The discovery of a viral cause of the disease came in 1983 from the labs of Luc Montagnier (recently won the Nobel Prize for this work) and Robert Gallo (recently didn’t win the Nobel Prize and is kind of pissed about it).

Genetic tests have shown that HIV originated in African monkeys and is related to a similar condition in monkeys called Simian Immunodeficiency Virus (SIV).  It is thought that the virus was passed on to humans through the consumption of “bush meat” in sub-saharan Africa where the virus acquired a taste for human hosts.


HIV Family Tree Credit: DOE

HIV is a retrovirus meaning it contains an RNA genome that it reverse transcribes into DNA.  Classically we think of DNA as the storage form of genetic information and RNA as the transfer or active form of this information.  For whatever reason, some viruses have switched these roles to their benefit.  HIV packs its own polymerase for the ride because host cells do not contain a protein that performs reverse transcription.   This process is highly error prone and is what accounts for HIV’s ability to rapidly become resistant to many antiviral treatments.  After conversion of its genome into DNA, HIV expressed another protein called integrase which causes the viral genome to integrate with the host’s genome to facilitate viral replication (making more nasty virus).  Once replication occurs, new viral particles can be released to start the cycle of infection over again.  This wouldn’t be so terrible, except for the fact that HIV destroys its host cell once it leaves.

HIV can be transferred through body fluids: blood, semen, vaginal fluid, and breast milk.  Once the virus enters the body, it seeks out host cells to infect.  Depending on the viral clade (a genetic classification), a virus will hunt down specific host cells for entry.  Once the virus runs into a cell that has the proper receptors, it can bind to this cell and enter.  All known HIV viruses bind to the CD4+ receptor on immune cells which include both macrophages and T-cells.  T-Cells are important for recognizing infections and directing other immune cells to kill the invaders.  This is why HIV is so devastating to the immune system, it inhibits the body’s ability to detect infection.  However, the story doesn’t end with the CD4+ receptor!  HIV also needs a second co-receptor to enter a host cell.  Depending on the virus, HIV can use the CCR5 or CXCR4 receptor to perform this function.  M-tropic viruses use the CCR5 co-receptor exclusively while T-Tropic viruses use the CXCR4 co-receptor.  Hybrid viruses have also been found that can use either receptor, but they aren’t nearly as common.  It’s these co-receptors that are important for the current HIV “cure” paper.  It has been known for some time that people who have a specific truncation mutation (make a much shorter protein)  in CCR5 called Δ32 are resistant to infection by M-tropic HIV viruses (and ONLY M-tropic viruses!).


Time course of HIV infection. Blue line CD4+ T-cells, Red line HIV RNA Credit: Jurema Oliveira/CC3.0

Now, back to the HuffPo story which is actually about a follow-up paper to a 2009 New England Journal of Medicine case report on the same patient.  Let’s just say this guy is extremely lucky, because this probably would never have gotten past an Institutional review board.  He presented with both AIDS and acute myeloid leukemia (AML).  AML is a cancer that completely messes up white blood cells and causes them to grow uncontrollably.  The treatment for this disease is to irradiate a person’s bone marrow to destroy all of their immune stem cells and then replace the destroyed bone marrow with marrow containing hematopoietic (relating to blood) stem cells from a matched healthy donor.  To treat this patient’s AML, the doctors switched out his marrow with a matched donor who just so happened to also have that awesome Δ32 mutation in their CCR5 gene!  To make a long story short, this guy now had completely new bone marrow, no cancer cells, and his immune cells now expressed a co-receptor which the HIV circulating in his blood could not use to infect his brand spanking new immune system.  How cool is that?!?! (It’s really cool)


Figure 1: The panel on the left shows the presence of antibodies to HIV proteins. 1) Control 2) Patient blood from before the transplant 3) Patient blood 650 days after the transplant 4) Negative control.  You will notice that the patient still shows antibodies for HIV 600 days after the supposed cure.  This could be due to suboptimal infection, but it's more likely some sort of immune system memory.  The panels at the right are a much better indicator of HIV infection (these graphs mirror the one above showing CD4+ T-cells vs HIV infection over time).  As you can see, after the stem cell transfer, the patient shows a dramatic decline in HIV RNA content (virus essentially lost) and his CD4+ T-cells have rebounded dramatically Credit: Hutter et al, NEJM 2009.

Figure 2: Patient T-cells can still be infected by T-tropic (CXCR4) viruses. Circles, CXCR4 tropic virus, Triangles, CCR5 virus Credit: Allers et al Blood 2010

As with any “cure” there are caveats. In the original NEJM paper, the researchers really only showed that CD4+ T-cell numbers were restored (CD4+ T-cells decline rapidly after infection) and no virus could be detected in the patient’s blood (See figure 1). In this most recent follow up, they show that the patient still has no signs of disease or latent infection in liver or brain tissue, but they also show another really cool experiment (maybe not cool for this guy). This patient’s cells are still susceptible to infection by T-tropic HIV viruses meaning if he comes into contact with an T-tropic or a hybrid strain, he’s screwed (Because those viruses don’t care about CCR5, they can use CXCR4)! I guess this last finding isn’t so exciting since it had already been shown to be the case. The original Δ32 mutant carriers discovered were a group of homosexual men who thought they were “immune” to HIV until they came into contact with a CXCR4 virus and all got HIV.

So, in summary, can we cure HIV with a simple blood stem cell transfer? Not really.  I think this is a viable option for people who are infected with M-Tropic viruses though.  If you are lucky enough to be infected with a susceptible viral strain, it might be something to look into to avoid a lifetime of highly active antiretroviral treatment (HAART).  One thing to keep in mind here, though, is that the best treatment for HIV is prevention.  This treatment may help some very lucky individuals, but it certainly isn’t a cure for the vast majority of people who suffer from this infection in sub-saharan Africa or other impoverished nations around the globe.  Hopefully we can come up with a much less invasive and cheaper cure that targets multiple viral tropisms.

###

Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. 2009. N Engl J Med. 12;360(7):692-8.

Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T. Evidence for the cure of HIV infection by CCR5{Delta}32/{Delta}32 stem cell transplantation. Blood. 2010 Dec 8

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Evie
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Excellent post Brian. Yea, that guy definitely hit the jack pot w the donor match. I look forward to a time when we know enough about genes, to be able to take an at home DNA test and know exactly what we're made of, what it means, and how to enhance it.

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