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Safe technique against HIV

1st April 2013


A UCLA AIDS Institute study has found that gene therapy can be developed as a safe and active technique to combat HIV. Researchers involved in this first-of-its-kind study found that cell-delivered gene transfer has the potential to be a once-only treatment that reduces viral load, preserves the immune system and avoids lifelong antiretroviral therapy. The study the journal Nature Medicine.

Though modest, the results do show some promise that gene therapy can be developed as a potentially effective treatment for HIV, said lead investigator Dr. Ronald Mitsuyasu, professor of medicine and director of the Center for Clinical AIDS Research and Education (CARE) at the David Geffen School of Medicine at UCLA.

Scientist Live spoke with Dr. Mitsuasu about his research.

What is OZ1 and specifially what HIV gene does it target?

OZ1 consists of a retroviral vector, an a gene for a ribozyme which targets the tat/vpr gene, which is highly conserved in all HIV viruses.

What is the mechanism behind its effects on HIV?

Once the gene is integrated in the host genome it can be replicated into new blood stem cells as well as in all the differentiated cells of the blood systems, including T-cells, monocytes, other white blood cells, red cells and dendritic cells. Once transcribed and translated, the ribozyme binds to the conserved region of the HIV tat/vpr, either free virus or integrated virus within the host DNA and then it "clips" the RNA or DNA at that site, thus making it unable to replicate or be transcribed. This effectively prevents new virus from being made by those cells which have the ribozyme incorporated and also inactives free virus which may not have yet integrated into host DNA, thus protecting those cells from being infected with HIV.

What vector did you use and why? Will you try a different one next time?

We used a modified murine retrovirus vector, derived from the murine Moloney leukemia virus. This vector does not contain the full MLV and hence cannot produce MLV virus. We were able to transduce on average, about 54% of all CD34+ stem cells in vitro. In the future we, and other researchers will likely use other vectors such as various lentivirus vector rather than retroviral vectors.

How did it perform in trials?

As the study demonstrated, we were able to show modest virologic effect and concordant increases in CD4 cells after ART was interrupted. It does not decrease HIV viral RNA to the same level as HAART, but then we didn't see that much free circulating gene marked cells after 40 weeks of follow up.

Can you explain the increase in CD4 count vs the lack of decrease in viral load?

As indicated in the paper itself, we were not able to demonstrate a statistically significant difference between the treated and control group in the primary endpoint, which was the viral load at 7 and 8 weeks after stoppiing HAART for the second time. This endpoiint was arbitarily picked and we may have seen a statiscially significant difference had we made the endpoint 12 instead of 8 weeks after stopping HAART. Nevertheless we did see statistically significant differences between groups when we evaluated the time-weighted area under the viral load-time curve (TWAUC) from baseline to week 40 and from baseline to week 100 and this correlated with a modest increase in CD4 counts as well. Hence there appears to be a signal indicating some antirviral activity. In addition, in those patients in whom we were able to detect some gene marked cells in the peripheral circulation, there was a correlation between more gene marked cells and better virologic suppression. We believe these findings are all consistent with a true antiretroviral effect of the gene therapy and we just need to find a way to get more marked cells into the patient and having them take hold and replicate in preference to unmarked cells in order to see more of an effect.

Could this gene therapy be done in conjunction with HAART?

Yes, we beleive that ultimately this treatment will serve as a adjunct to ART and may allow patients to remain off ART for longer periods of time.

What can be done to increase the efficacy of the therapy?

To increase the effect, we will need to be able to get more gene marked cells to engraft, perhaps by using some form of pre-gene therapy conditioning of the patients, as is done in bone marrow stem cells transplants, and finding better ways to apply selective pressure so that these cells proliferate in preference to the unmarked cells. These parameters will be worked out in future smaller scale trials. Also, we will likely use more than one gene to target multiple sites in HIV.

Can you place this trial within the context of other HIV therapies, particularly gene therapy approaches?

As indicated above, at this time, gene therapy cannot be considered a good enough replacement for traditional HAART, but with further improvement in the technology and methodology of gene transfer, we may ultimately get to a point where this may be a viral alternative treatment for HIV.

Finally, what can be taken from this trial? 

The take home message, is that in a controlled randomized clinical trial, that using gene therapy for HIV can induce some degree of antiviral effect against HIV and that with further improvements, this may, at some point,.become an effective treatment for HIV.

(Reporting by Marc Landas)





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