A recent report published on stem cells (from umbilical cord blood, peripheral blood) and HIV recently prompted me to find out exactly what this branch of research involved and how 70 HIV positive patients in California fared with this elegant and hopeful combination of molecular biology and cellular biochemistry.
It was elucidated that an enzyme known as "ribozyme" (as seen in above picture) could be created with an activity that enables it to cleave the mRNA* strand of the HIV-1 virus (*mRNA stands for m=messenger RNA= RiboNucleic Acid). mRNA is an important component in viral replication as it serves as a "template" strand which codes the proteins to form the structures of many more HIV viruses. Essentially, if you can halt the formation of the template, you can prevent the formation of any meaningful viral particles, rendering the virus non-infectious. The ribozyme acts as a special biochemical scissors to snip the template at specific sites and prevent template formation and further virus manufacturing.
Research on this area of enzymic activity has been conducted for more than a decade now, since the early 90's and much funding has been contributed to finding an effective vaccine. The reasons why a vaccine has remained elusive for so long are:
(1) Understanding of viral replication & its susceptible points
(2) Mutation of the HIV virus genes (i.e. different mRNA's need different types of scissors)
(3) Different strains of HIV (different gene coding, which strain is more important?)
(4) Possible side effects of vaccines on a weakened immune system
What lead researcher Ronald Mitsuyasu of the University of California, Los Angeles’s Center for Clinical AIDS Research and Education and UCLA virologist Jerome Zack did was to engineer a ribozyme especially for the cleavage of HIV-1 mRNA at various sites, attach the ribozyme sequence to a mouse viral vector (penetrates human cells to deliver its genetic contents but is otherwise harmless) and expose it to human bone marrow and peripheral blood stem cells.
"The mouse virus carries the enzyme into a cell, where it becomes part of the cell’s natural machinery and fortifies it against any attempts by HIV to infect it and begin making viral copies. The stem cells are then reinserted into the donor’s body, where they begin making numerous copies of immune system cells that are resistant to HIV. This effectively prevents infection of the cell and if already infected, prevents its ability to pass on the infection.
The HIV virus attacks several different types of blood cells that are part of the immune system. "If you can target the blood- forming stem cell, that cell gives rise to all blood cells," said virologist Jerome Zack of UCLA. "So, therefore, if you could protect that cell, then every other cell derived from that would be protected."
Dr. Zack hopes stem cell therapy could be a better strategy for fighting the virus.
Dr. Mitsuyasu recently finished an initial clinical trial to test the safety of the treatment. The 10 patients in the trial didn't have any problems, and after three years, the HIV-resistant blood cells could still be detected.
Dr. Mitsuyasu is currently enrolling people in a trial to test the stem cell therapy. Patients are first given a growth factor (GCSF) that stimulates bone marrow stem cells to enter the bloodstream. Then blood is drawn and the patients' own stem cells are isolated from the blood. Next, the gene is inserted into the cells by a modified, harmless virus related to HIV. Then the stem cells, armed with their new weapon, are returned to the bloodstream where they begin making all the different types of blood cells, each of which will inherit the new anti-HIV gene.
According to the article, the method can protect about 10 percent of the patients' stem cells, but as the HIV virus slowly kills the vulnerable cells and protected cells continue to replicate, the percentage will increase. To speed up the process, six months after receiving the infusion of modified cells, patients will stop taking their antiviral medications for four weeks to give the HIV virus a chance to kill off some unprotected blood cells, putting pressure on the protected cells to replicate faster.
This exposure process is repeated again after 12 weeks when the patients go off their medication for at least eight weeks, and potentially longer depending on how well the strategy works to reduce the level of HIV in the patients' blood.
"If this works, even though it may not cure the disease, it certainly would allow patients to go for periods of time without therapy," Dr. Mitsuyasu said. "And that will make a big difference both in terms of the rate at which resistance develops to these medicines as well as all the side effects associated with having to take the medicine for the rest of their lives."
If this model can be developed for HIV, it also has great potential for use in other viral therapies affecting other types of rapidly regenerating stem cells in other organs. I'll mention a little more about how stem cells have been used in treating HIV patients in another entry... this one's getting a little long :).
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