HIV infection causes its devastating effects on patients by
destruction of the CD4 T helper cell and macrophage component of the immune
system. Entry of the virus into these cells occurs via binding to the molecules
CD4 and CCR5. Interestingly a group of patients who appear to be resistant to
HIV infection have a mutation in the CCR5 protein. Studies conducted on these
patients have demonstrated that the mutation in CCR5 results in resistance to
infection, while other components of the immune system of these patients are
intact. Thus one possible method of treating HIV would be if somehow one could
induce the CCR5 mutation that is protective from HIV into the immune cells of
patients. It is very difficult to selectively mutate established immune cells,
however, one possibility would be if one could induce such a mutation in stem
cells, and then administer the stem cells to the patient so that they
"differentiate" into immune cells.
Scientists from the Department of Microbiology, Immunology
and Molecular Genetics, at the David Geffen School of Medicine, University of
California at Los Angeles have started figuring methods of doing this.
Specifically, a new technology called "RNA Interference" was used to selectively
block expression of the CCR5 gene on stem cells. RNA interference is a process
that is normally used by mammalian cells to protect themselves against viruses.
Specifically, RNA is found only as a single strand in mammalian cells. Double
stranded RNA is found only in viruses. When a mammalian cell recognizes double
stranded RNA it believes that a viral infection is occurring and two processes
are triggered. The first is gene-nonspecific. Regardless of what is coded in
the double stranded RNA, the cell starts to produce the protein interferon,
which blocks other cells from being infected, as well, the cell alters various
metabolic activities and enters a quiescent state. The second process is
gene-specific, in that the cell will destroy any other RNA that resembles what
is encoded in the double strand. While the first effect is useful for
inhibition of viral infections, it is non-specific and causes general toxicity
when administered at high enough levels to people or animals in order to elicit
an effect. Thus a Nobel Prize was awarded in 2006 to Fire and Mello when they
discovered that by administering pieces of double stranded RNA shorter than 21
nucleotides, the selective gene-silencing effect could be induced in absence of
the non-selective "interferon effect".
In their recent paper, Liang et al used RNA interference to
block expression of the CCR5 gene on stem cells that are capable of giving rise
to both CD4 T cells, as well as macrophages. They demonstrated that
gene-blockade was passed on to the progeny of the stem cell, and that the newly
generated cells were resistant to HIV infection in vitro.
In contrast to using stem cells for hematopoietic
transplantation, in which depletion of the original recipient cells is required,
the use of genetically engineered stem cells for treatment of HIV would not
require such myeloablation since the HIV infection will naturally be killing the
non-manipulated cells.