Human
immunodeficiency virus (HIV) is a retrovirus that causes AIDS. The virus infects cells of the immune system T
helper 1 CD4+. Glycoprotein gp120 on the viral envelop binds to receptor CD4 and
co-receptor CCR5 on a surface of Th, which causes conformation change of gp120,
allows gp41 to unfold and insert hydrophobic terminus in cell membrane. This allows
the virus to enter the cell where reverse transcriptase makes ds DNA. Then
integrase cleaves DNA on both ends creating sticky ends and transfers it to the
nucleus where the viral DNA is randomly inserted in the host cell DNA. At this
point the virus establishes latency. However, once immune system becomes activated,
virus starts replicating, further infecting immune cells.
There
are about 33 million people living with HIV. It kills about 2 million a year. About
10% of world population (mostly Caucasian) is immune to HIV, which gives prospective
in search for new HIV treatment and potentially a vaccine. Research is focused
on few proteins that are associated with HIV resistance.
CCR5
is receptor found on human immune cells. It acts as a lock for HIV’s “key”
gp120. A mutation on the gene coding for
CCR5 called delta 32, it has to be inherited from both parents in order to be
completely immune (double delta 32). With this mutation HIV will not be able to
enter the cell. New England Journal of Medicine published a case in 2009,
describing a patient with leukemia and HIV undergoing bone marrow transplant
from a donor with double delta 32 CCR5. After the procedure he had neither leukemia
nor HIV.
Followed
by this case, new studies showed that mice with delta 32 were immune to HIV. The
researchers took mice already infected with HIV and ejected them with stem
cells containing delta 32 CCR5. Later they found that mice were able not only
fight HIV and other infections, but also completely destroy HIV. Because of
stem cell ability to reproduce indefinitely, they could completely replace normal
CCR5 immune cells with HIV-resistant immune cells. This procedure is currently
being tested in Phase 1 human trials.
Mutation
on CCR5 is found in about 10% of Caucasian people. Scientists are trying to
answer question on when and why mutation occurred. Many studies showed that mutation is traced
back to 12th-15th century to the bubonic plaque wave. Some
researchers suggest smallpox is the cause for mutation because it was around
much longer and killed more people. It was also found that the mutation reduce hepatitis
B virus. Researchers concluded that the driving force behind the mutation is a
group of infectious diseases, rather than one deadly pathogen.
There are other factors that may account for HIV immunity. Protein called cystatin could be one of them. Researchers studies Kenyan women who were HIV-free after working as prostitutes for three years. They found these women had increased levels of cystatin, a protease inhibitor, knows to interfere with HIV ability to reproduce.
Some
studies showed that people with certain type of HLA, particularly B27 and B57,
are able to attack and kill HIV. These people, called “elite controllers” despite
being infected with HIV, may never experience any symptoms.
Another
protein that is gaining attention is CD4. Some believe that is would be a much better
target for drug development than CCR5, because it always must be accessible for
HIV to get in the cell.
References:
http://www.livescience.com/9983-immune-hiv.html
http://www.nature.com/news/2010/101104/full/news.2010.582.html
Immunity to HIV is interesting, especially because the majority of these people have a "mutation" on CCR5. And the question to how this variant came about is much debated. As you mentioned the plague is a thought. My thought, since 10% of the population has this "mutation", I would call it a polymorphism as opposed to a mutation. And the originating source of the "mutation" may not be identifiable.
ReplyDeleteAs for CD4 as a better target in drug development, I would believe it would have to be dependent on what stage and how it is used. As I am not an immunologist, my reasoning could be very flawed, but here is what I think:
In late stage HIV infection it has been reported that CXCR4 may become the more important site (as opposed to CCR5), indicating that CD4 may be the better target in late stage, but it seems that CCR5 is still a good target in early stage infection. Potentially, in late stage, if treatment with a CD4 inhibitor for an appropriate duration (half life of CD4 cells seems to be somewhere around 3-4 weeks-- though, it is mentioned that the half life is reduced in HIV+ CD4 cells) and then followed by injections with stem cells (no CD4 inhibitor so they are functional) may potentiate a beneficial treatment. But just a thought.
Anyway it seems like there is great potential to treat HIV patients, but vaccinations are seemingly difficult to produce.
The origin of the CCR5 delta 32 mutation is such an interesting topic. There are few theories out there. Some think it's smallpox or bubonic plague. Dr. Christopher Duncan from University of Liverpool suggested that it's not Bubonic plaque since BP is a bacterial infection that doesn't use CCR5 delta 32. But rather a series of plagues epidemics of viral, hemorrhagic fever that used CCR5 to enter target cells. They suggest the single mutation occurred over 2500 years and the epidemics of plagues forced the frequency to increase.
ReplyDeleteAnother interesting fact about CCR5: even though CCR5 Delta d32 protects against HIV, it makes the carriers more susceptible to WNV. And a recent study in Iran showed that CCR5 D32 individuals might have increased risk of developing MS.
References:
S R Duncan, S Scott, C J Duncan. Reappraisal of the historical selective pressures for the
CCR5-D32 mutation. J Med Genet. 2005
Majid Shahbazi, Hamid Ebadi, Davood Fathi. CCR5-Delta32 Allele is Associated with the Risk of Developing Multiple Sclerosis in the Iranian Population. Cell Mol Neurobiol. 2009