Personalized Medicine: A Cure for HIV

Personalized Medicine – finding the right treatment for the right patient at the right time – is quickly becoming a buzzword both in the medical field but also to the public. But is it just hype? No!  I discussed a number of examples of how personalized medicine is currently be used in breast cancer in a previous post. In this and future posts, I’ll talk about a few fascinating emerging examples of the promise of personalized medicine.  These are NOT currently being used for patient treatment as part of standard of care, but could be someday.

HIV

HIV lentivirus

The Human Immunodeficiency Virus (HIV), the cause of AIDS, is a virus that attacks the immune system.  This attack prevents immune cells from fighting other infections.  The result of this is that the patient is more likely to acquire other infections and cancers that ultimately kill them.  When first discovered in the early 1980s, HIV infection was a death sentence. Untreated, survival is 9 to 11 years.  In the past 30 years, antiviral treatments have been developed that, when taken as prescribed, essentially make HIV infection a chronic disease, extending life to 25-50 years. But there is no cure for HIV, and as of 2012, over 35.3 million people were infected with the virus.

The lack of a vaccine to prevent the disease or of a cure to treat those infected isn’t because no one is trying. Since the virus was identified as the cause of the disease, scientists have been working to find a prevention or cure (along with developing all of the antiretroviral drugs that delay/treat the disease). I’m not going to discuss all of this interesting research (though it is worthy of discussion), instead I’m going to talk about one patient, Timothy Ray Brown, who was cured of HIV/AIDS through a stroke of genetic understanding and luck!

Brown was HIV positive and had been on antiretroviral therapy for over 10 years when he was diagnosed with leukemia in 2007. His leukemia – Acute Myeloid Leukemia (AML) – is caused by too many white blood cells in the bone marrow, which interferes with the creation of red blood cells, platelets and normal white blood cells. Chemotherapy and radiation are used to treat AML by wiping out all of the cells in the bone marrow – both the cancer cells and the normal cells. Brown’s doctors then replaced the cells in the bone marrow with non-cancerous bone marrow cells of a donor.  This is called a stem cell transplant, and it is commonly used to treat leukemia – often resulting in long term remission or a cure of the disease.

But the really cool part of this story isn’t the treatment itself.  Rather it’s that that Brown’s doctor selected bone marrow from a donor that had a mutation in the gene CCR5. So what? The CCR5 protein is found on the outside of the cells that the HIV virus infects. CCR5 is REQUIRED for the virus to get inside the cell, replicate, and kill the cell. Without CCR5, HIV is harmless. There is a deletion mutation in CCR5 called delta32 that prevents HIV from binding to the cell and infecting it.  Blocking HIV from getting into the cell prevents HIV infection.  In fact, it’s been found that some people are naturally resistant to HIV infection because they have this deletion. Two copies of the gene are found in 1% of the Caucasian population, and it’s thought that this mutation was selected for because it also prevents smallpox infection.
HIV_ccr5So Brown’s doctors repopulated his bone marrow with cells that had the CCR5-delta32 mutation.  This didn’t just cure his leukemia but it also prevented the HIV from infecting his new blood cells, curing his HIV. He is still cured from HIV today!

What does this mean for others who are infected with HIV? Is a stem cell transplant going to work for everyone?  Unfortunately, no. This mutation is very rare, so finding donors with this mutation isn’t feasible.  Plus, this is a very expensive therapy that comes with risks such as graft-versus-host disease from the mismatch between the person receiving the transplant and the transplanted cells themselves. However, there are possible options to overcoming these challenges, including “gene editing.” In this method, T cells from HIV-positive patients would be removed from the body and then gene editing would be used to to make the CCR5-delta32 mutation in these cells.  These cells could then be re-introduced into the patient.  With the mutation, HIV won’t be able to infect these T cells, which would hopefully cure the disease, while avoiding some of the major graft-versus-host side effects. A small clinical trial tested this idea in 2014 (full article can be found in the New England Journal of Medicine), and HIV couldn’t be detected in one out of four patients who could be evaluated. Although this is a preliminary study using an older gene-editing technique, it shows promise for “personalized gene therapy” to potentially cure HIV.

What happens when chromosomes rearrange? Sometimes cancer.

There are so many different kinds of genetic mutations.  So far, we’ve only discussed small single nucleotide changes and insertions and deletions.  But entire pieces of chromosomes can also be rearranged in what’s called a translocation. The prefix “trans” shows up a lot in science.  It comes from Latin and means “across” or “on the opposite side”.  “location” is physically talking about the chromosomal location.  So “translocation” mean s pieces of chromosomes moving to another location.

translocation

You can think of it as two different pieces of DNA that aren’t usually right next to each other, being put next to each other. Kind of like a centaur – the top of a human attached to the bottom of the horse – a human/horse translocation.  Of course, in the case of chromosome, genes or regulatory pieces of DNA are moved next to each other, and although it may not seem nearly as dramatic as a centaur, the effects can be just as surprising.

philadelphia chromosomeOne example of a translocation that has dramatic consequences is the translocation that causes the blood cancer Chronic Myelogenous Leukemia (abbreviated as CML).  In this case, part of Chromosome 9 and part of Chromosome 22 break off and swap.  So now, Chromosome 9 has part of chromosome 22 attached, and vice versa.  The part of chromosome 22 and the broken off part of chromosome 9 are called the Philadelphia chromosome, and this is what causes the leukemia.

But how?  We  imagine that Chromosome 9 and Chromosome 22 are both train tracks.  On those train tracks are trains that can either be going or not going depending on the upstream signals.  On Chromosome 22 there is a green signal that is stuck at green so the train is always going.  On Chromosome 9, there is a more sensitive signal – some times it’s green, but most of the time it’s red so the train isn’t going.

train_anaolgy

What happens now is that there is a switch (or a translocation) that attaches the Chromosome 9 and 22 train tracks together.   But when it does this, the green signal from Chromosome track 22 is telling the train on the chromosome 9 track to go – even though it usually doesn’t always go.  This is nearly exactly what happens in the case of the Philadelphia chromosome, except the trains are genes that are making protein (if the signal is green) or are not made into protein (if the signal is red). The signals are parts of DNA that regulate the “expression” of the gene (in other words, whether or not the gene makes the protein).

train_analogy_switch

In the case of the translocation in CML, what happens is a gene of Chromosome 22, called BCR is attached to part of the Abl gene on chromosome 9.  In this configuration, the BCR-Abl fusion gene makes a protein that is always “on”.   What does this protein do?  Essentially, it tells the blood cells to keep growing and dividing.  This makes too many blood cells and causes leukemia.

There are many different chromosomal translocations that cause a number of different diseases, but what they have in common is either creating a protein that is always on or changing the upstream signal that tells a gene to make more protein.  Most of the time, this results in signalling the cell to keep growing and dividing, which is why translocations are often associated as a cause of cancer.