In the longer term, scientists believe we may one day be able to deliver these small bits of RNA into cells in order to stop HIV from reproducing. Some scientists feel that we may also be able to intervene in the short-term, by stopping our own CD4+ cells from producing a surface receptor that HIV requires in order to infect these cells. RNAi therapy holds promise not only for treating HIV disease, but also for common infections like hepatitis B and C. Early results from treating hepatitis in animals have been encouraging.
HIV uses proteins on the surface of immune cells, like CCR5, in order to infect the cell. RNAi therapy aimed at blocking this process would target the gene in an immune system cell responsible for making CCR5. In this case, the RNAi therapy sends a "fake" gene that exactly matches the targeted CCR5 gene. When the CCR5 gene starts making the CCR5 protein, it also creates a set of instructions called messenger RNA or mRNA. RNAi attaches to and silences the mRNA before the message can be received. Once the message is silenced, RNAi seeks out more mRNA and silences more messages, stopping the production of more CCR5. As a result, an important protein that HIV needs is not produced, severely crippling its ability to infect a cell.
CCR5 is considered a prime target for RNAi therapy because, so far, its absence has no apparent effect on human health. Eliminating CCR5 may decrease the number of cells that HIV could get into with hopefully no serious side effects for the person. In one recently reported lab study, HIV activity in an immune cell called a macrophage was silenced by RNAi therapy for up to three weeks.
RNAi therapy that is designed to stop reproduction of HIV once it gets inside cells will require that the "fake" gene exactly match the HIV gene that it targets for silencing. Because HIV makes inexact copies of itself (mutates) each time it reproduces, targeting HIV genes directly with RNAi might be challenging. It may be prone to the same kind of resistance problems that are seen with anti-HIV drugs. However, in lab studies, RNAi aimed at HIV genes can readily block HIV reproduction.
Messenger RNA made by any HIV gene is also a possible target for RNAi therapy. Experiments have shown that the tat, rev, gag and pol genes in HIV are all possible targets. RNAi appears to thrive for a long time and can continue targeting virus over and over. In test tubes, one treatment can produce results lasting up to ten days.
Pioneering research has produced the first successful RNAi treatment of a viral disease in a living animal: hepatitis in mice. Judy Lieberman, M.D., and her team silenced the fas gene that is involved in nearly all types of hepatitis. This gave protection from liver cell death (cirrhosis) for up to ten days after a single treatment. The fas gene triggers cell death. So, turning off the fas gene and stopping cell death meant survival for mice with hepatitis. The untreated mice died of hepatitis within three days, while 82% of the mice treated with RNAi survived with normal livers. Their liver cells were protected for ten days. The effect of the treatment began to wear off after 14 days and disappeared after 21 days.
Challenges still remain as RNAi research moves from mice to man. Finding the right genes to target is critical. How to get RNAi to the cells where they need to target remains unanswered. Also, the short- and long-term side effects of RNAi therapy are largely unknown, but they probably carry some of the same concerns as other gene therapy. Those include risks of abnormal cell growth (cancer) and the methods (often viruses) that are used to get genes into cells.
The possible benefits of treating HIV with RNAi therapy offers hope. The suspected long-lasting effects of RNAi could decrease the daily demands of anti-HIV therapy. While using RNAi therapy to target HIV genes will likely be researched at first together with anti-HIV drugs, it's possible to imagine a once- or twice-a-month therapy as the new (or only) drug in your regimen.
Also, RNAi therapy may offer protection in HIV-infected cells that are not actively making virus. These are believed to be reservoirs for HIV infection. If or when these cells begin producing HIV again, the RNAi already present in the bloodstream should immediately target and shut down HIV reproduction.
Aiming RNAi therapy at the genes of a virus is unlikely to create toxic side effects, since those genes do not create products that are necessary for a person to live. And because there are many possible targets for RNAi -- perhaps all HIV genes at once -- strategies with more than one RNAi approach could shut down HIV activity for long periods.
It is likely that hepatitis B and C will be early targets for RNAi therapy, given the direction of the research. As well, tuberculosis and other opportunistic infections may be among its next targets. It's too early to throw out the anti-HIV drugs, but the pipeline of new anti-HIV strategies has just gotten fuller. Human studies of RNAi are expected to begin in the next two to three years.