In a novel approach to HIV/AIDS therapy, researchers from UC Davis have engineered mice with human stem cells resistant to HIV infection.
The natural history of HIV infection involves the slow destruction of the host immune system, eventually predisposing the infected patient to a multitude of infections and malignancies- clinically recognized as the syndrome AIDS. Anti-retroviral drugs, which are currently the mainstay of HIV treatment, have been quite successful in delaying the progression to AIDS. The drugs, however, have to be taken indefinitely and require faithful adherence on the part of the patient. In addition, there is a risk of developing resistance to the drugs with prolonged use and the side effect profile of many of these drugs is less than acceptable.
Research goal is to make immune stem cells resistant to HIV.
In a novel approach to targeting HIV, researchers over the past few years have been attempting to create human stem cells (precursor to the mature immune system) that would be resistant to HIV. The hope has been that these cells could be transplanted to an HIV positive patient and would go on to develop into a functioning immune system which would remain resistant to HIV. Taking an important step in the realization of this premise, researchers at UC Davis recently tested the application and effectiveness of this approach in mice.
In the study, published in the May issue of the Journal of Virology, researchers used gene therapy and viral vectors to modify human immune stem cells to express three different anti-HIV genes. The anti-HIV genes target various stages of the HIV life cycle- preventing its integration and replication in immune cells. The stem cells were then transplanted into mice with a compromised immune system (similar to that of a HIV positive patient). The stem cells went on to differentiate along the various mature cell lines and proliferate into a normally functioning immune system. During the second phase of the study, the mice were exposed to live HIV. Supporting the researchers expectations, it was observed that mice which had been engrafted with the HIV resistant immune cells were protected from infection.
The study has shown the feasibility of two crucial steps required for stem cell therapy to be successful. First, the genetically modified immune stem cells can differentiate and proliferate in the host to create a normally functioning immune system. Secondly, when exposed to HIV, the immune system remains protected from infection.
Plans for human clinical trials
Researchers hope to replicate the above results in human clinical trials. If successful, HIV positive patients could be expected to be engrafted with HIV resistant stem cells (researchers expect one stem cell transplant would likely be sufficient) and develop and maintain a normal immune system, delaying or even halting the progression to AIDS. While some level of HIV replication may continue, it is likely to be clinically insignificant. Once treated, the patients could be expected to stop taking their anti-retroviral drugs.
While human clinical trials have yet to begin, critics argue that an individually tailored therapy such as this is likely to be impractical and quite costly to provide for the millions (and counting) HIV positive patients. While the long term potential and benefits of using stem cell therapy to target HIV is yet to be seen, the underlying scientific premise of the approach is undeniably novel and will have consequences in the medical field beyond HIV.
J. E. Walker, R. X. Chen, J. McGee, C. Nacey, R. B. Pollard, M. Abedi, G. Bauer, J. A. Nolta, J. S. Anderson. Generation of an HIV-1-Resistant Immune System with CD34 Hematopoietic Stem Cells Transduced with a Triple-Combination Anti-HIV Lentiviral Vector. Journal of Virology, 2012; 86 (10): 5719