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It has been known for many years that T cells that are more
activated, which means they display markers on their surface like CD38 which
show how responsive they are to infections, and more differentiated, which means
they display markers such as CD45RA stating that they have developed specialized software
ability of cell destruction, are much more likely to be infected with HIV than cells
who are at rest and undifferentiated.
Dr. Asier Sáez-Cirión of the Pasteur Institute found that
The vulnerability of cells to HIV infection also depends on the metabolism (energy) of the cells.
requirements; in particular, how fast they burn glucose. His team made a series
experiments that showed that, on the whole, cells that were more activated and
differentiated also burn glucose faster, which is predictable, as they do
no more work.
They took T cells and were able to infect 12% of them in the
laboratory dish. The most differentiated cells, the T-effector memory cells, were the most
susceptible to infection, with 20% infected.
But above all, 0.9% of the least active and less
differentiated cells, T-naive cells, were also infected. The only thing that
distinguished these weak activation but the infected cells was that they had exceptionally
high energy demand for cells of their type.
An interesting aspect of the role of glucose metabolism in
HIV infection is it seems to continue
replication, rather than the first infection. For HIV infection to occur,
cells must express on their surface the CD4 and CCR5 receptor molecules, which
are present in higher density on more differentiated cells. But to continue,
productive infection to maintain the cell must also continue to burn glucose
at a high rate, and indeed viral production peaked in these cells about three to
five days after the initial infection rather than immediately. So the drug that
interfered with glucose metabolism may act at a different stage of the virus
time line as the inhibitors of entry.
Scientists have therefore grown infected cells with
several drugs that inhibit glucose metabolism. Such drugs could be a problem
significant threat of toxicity because they interfere with one of the most fundamental
and universal biological processes.
However, they found that a modified version of glucose,
2-deoxyglucose or 2-DG, "decrease in HIV infection of CD4 T cells with a minimum of
cellular toxicity. "This molecule looks like glucose to cellular receptors but can not
crack to release energy in the same way as ordinary glucose. Its specific effect
was to reduce the ability of the cellular machinery to produce viruses
Components. Interestingly enough, the 2-DG worked retrospectively – he closed the virus
replication in cells even though they had been infected eight hours earlier, and
it's done so effectively that it has actually reversed potential new infections.
If HIV succeeds in infecting low-activity cells and
differentiation, they are more likely to turn into quiescent "reservoir" cells
that are potential sources of future waves of viruses rather than cells currently
producing a lot of viral particles. Importantly, 2-DG reduced the number of two
reservoir cells and actively productive cells.
2-DG was considerably less toxic than other metabolic inhibitors
tried by the researchers. This seems to be due to the fact that even if it caused a "glucose starvation"
who killed the T cells, he was more likely to kill HIV-infected cells than
uninfected cells, probably because their energy needs are greater.
Dr. Sáez-Cirión's team did not just do experiments on cells
infected in the laboratory dish; they also took T cells from six HIV-positive people on antiretrovirals
treatment, added a chemical agent of cellular activation, then 2-DG. Glucose
The badog powerfully prevented the T cells from reactivating and producing new
virus.
These experiments are preclinical and preclinical
surveys, and many steps will be needed to find out if the metabolism use
inhibitors are safe. But they found
a new vulnerability of HIV to a clbad of molecules that has
have already been studied in the treatment of cancer and are simple, easy to manufacture. The fact that they work on cellular rather than viral machines
suggests that viral resistance might not be a problem, and they can hold the
potentially useful as agents that can preferentially kill HIV-infected reservoir cells.
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