Tuesday, 25 March 2014

Shutting the door to HIV? (part 1 of 2)

Earlier this month a study was published that suggested a potential new approach to treat HIV infection using genetic modification of the T-cells HIV infects. This study rightly generated media interest, so I thought I’d give my take on it and outline some of the details. I’ve divided the post into two parts, allowing for an ample amount of background to aid understand of the details of the study, without scaring you off with one long post.

To begin with, a bit of cell biology. A protective layer of lipid molecules, in a double sheet, surrounds our cells. This ‘lipid bilayer’ provides separation between the inside and outside of the cell. However, cells needs to interact with the environment and transport molecules across the lipid bilayer. One of the major mechanisms to have evolved are cell surface receptor proteins. These proteins reside in the lipid bilayer, exposed to the environment, and can bind molecules, in some cases these are then transported into the cell. These proteins are essential for the normal functioning of our cells.
A schematic of a lipid bilayer with inserted proteins
spanning it (transmembrane proteins)

Like other viruses, HIV must enter cells to replicate. Without wanting to overly anthropomorphise the situation, viruses are devious in the ways they do this. In the case of HIV, binding to two cell surface receptors drives a shape change in a protein on the virus that causes it to fuse with the lipid membrane of the cell. This fusion event allows entry of the viral genetic material, which can then undergo replication.

CD4 is the essential receptor for HIV; it is the first receptor the virus interacts with. CD4 is a protein expressed by cells of the immune system, such as T-cells and macrophage. Once bound to CD4, the virus must bind to one of two co-receptors, either CCR5 or CXCR4. When this second binding event has occurred, the shape change will happen, and the virus will fuse with the cell and enter.
HIV fusion

The vast majority of viruses that are transmitted between individuals, and many of the viruses within an individual are CCR5 tropic (they bind CCR5 and not CXCR4). You could therefore speculate that without CCR5, HIV transmission would be blocked, and infection levels reduced. Without CCR5 on cells, could we shut the door to HIV infection? However, an important question is whether this would be safe? Can people survive without CCR5?

Interestingly, around 4-16% of people with European descent have a mutation in at least one copy of the CCR5 gene (CCR5 – italics denote a gene) known as CCR5 delta 32 (there is deletion of 32 base pairs from the gene). People with this mutation in one gene copy, 'heterozygotes', express roughly half the level of the protein compared to a person with no mutation. It is also possible to have the delta 32 mutation in both copies of the gene, 'homozygotes', leading to no CCR5 protein being present on any cells – and these people are perfectly healthy. What’s more, people carrying CCR5 delta 32 mutations have resistance to HIV infection, and slower progression to AIDS if they are infected, particularly the homozygotes.

The hypothesis that disruption of CCR5 could be protective was further strengthened in 2008 with the ‘Berlin patient.’ This individual, later disclosed as being named Timothy Rae Brown, has been functionally cured of HIV. Brown was diagnosed with HIV in 1995, and was subsequently diagnosed with a leukaemia in 2006. The leukaemia could be treated with a bone marrow transplant. Brown’s doctor, Gero Hütter, decided to acquire the bone marrow from a donor homozygous for CCR5 delta 32. Stem cells of the immune system reside in bone marrow; so receiving bone marrow from a homozygous CCR5 delta 32 individual meant Brown developed an immune system populated by cells containing the mutation. In 2009, Brown had been off his antiretroviral therapy, used to treat HIV, for over a year and had had no detectable virus. He remains, to this day, free from antiretroviral therapy and still has no detectable HIV.

As amazing as the story of the Berlin patient is, bone marrow transplants are not a realistic option to treat HIV infection because of cost and the risks associated with the procedure. However, what if there were other, less drastic, ways of introducing mutations to CCR5?

This is where I’ll leave the first part of this post. Tomorrow I’ll post part two looking in detail at a study assessing the safety of genetically modifying cells to cause deletion of CCR5, and to see the impact this has on HIV infection. So come back tomorrow for more…

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