Understanding HIV:
CCR5 and fusin—co-receptors for HIV
January 2003 View PDF En
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Clinical Implications
While these findings may not have direct therapeutic relevance
at present, they do have some interesting clinical implications
for research and treatment in the future. Studies have suggested
that some long-term non-progressors have defects in the CCR5 receptor
protein and appear to have some immunity to HIV infection.
The study showed that when people inherited a defective version
of CCR5 from both parents, they appeared to be resistant to infection
with HIV. (The gene is considered defective because a portion of
it is missing, and it thus cannot produce a functional CCR5 receptor.)
Some people may inherit a single defective version of the gene from
one parent, but there is insufficient information to know whether
this confers partial protection against infection.
It has been shown that people with the partial CCR5 defect may
progress to HIV disease more slowly than someone without the CCR5
defect. This study was extremely small, however, and the defective
receptor was found in only two of fifteen people who were thought
to be exposed to HIV, yet remain uninfected.
Researchers are already experimenting, in test tubes, with approaches
that may be useful in blocking the CCR5 and CXCR4 receptors. Two
approaches are possible. One is to artificially give more of the
chemokines to people whose CD8+ cells are not producing these chemicals
in adequate quantities. The other is to develop methods for directly
blocking the receptor sites. Both therapies should help prevent
HIV from infecting new cells.
The challenge of either approach is to do this without interfering
with the normal function (whatever it is) of the chemokines and
the CCR5 receptor sites. Thus far, no known harmful side effects
have resulted from the defective gene, in humans, as well as in
animal studies. The CCR5 receptor appears to be “non essential,”
meaning that binding up the receptor is not expected to interfere
with normal immune function. CXCR4, on the other hand, may be more
critical. Mice with cells engineered to be CXCR4 deficient died
during gestation.
Another potential therapeutic use of these defective CCR5 genes
is in stem cell transplantation, where stem cells (the mother of
all cells, which divide into the entire spectrum of immune cells)
are removed from an individual who has the defective gene and then
reinfused into a person with HIV who does not have the defective
gene. If stem cells with two copies of the defective CCR5 gene could
be successfully transplanted into an HIV-infected individual, they
would produce blood cells (lymphocytes and macrophages) that would
be naturally immune to HIV infection, although only to infection
by NSI strains of HIV.
Another application for these discoveries is the development of
better animal models to study HIV disease. A limitation in studying
the disease and potential therapies in animals has been that HIV
does not infect many animals, and in those species which are infected,
HIV rarely causes the immune decline and disease as it does in humans.
Engineering animal cells with CCR5 and CXCR4 may provide a way to
better research the disease and study potential therapies more efficiently.
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