A blog about science because it's a wonderful thing. No real theme, just topics I chose to write about because I understand them (biological science, mostly to do with viruses). I am a PhD student in Cell and Molecular biology, studying immune defence to viral entry, at University College London (credentials). Enjoy...
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.
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…