Mar 06 2014
I have argued that HIV treatment is one of the shining examples of the success of reductionist modern medicine. In three decades we went from knowing nothing about a new disease that was almost universally fatal over a few years, to having an extensive understanding of the disease and reducing it to a manageable chronic illness. We still have not created an effective vaccine, nor have we figured out how to cure the disease entirely, but those are both active research programs with promising results.
Recent developments show how sophisticated our technology is becoming. Researchers just published a safety study in the NEJM in which they took the white cells from patients with HIV, treated them to make them resistant to the virus, and then transfused them back into the patients. There was one serious infusion reaction, but otherwise the procedure seemed safe.
HIV enters T-cells (part of the immune system) by attaching to a coreceptor called CCR5. There are rare individuals who have a mutation in the CCR5 gene which makes them resistant to HIV, demonstrating how important the receptor is to the life cycle of HIV. Researchers at the Clinical Cell and Vaccine Production Facility at the University of Pennsylvania used used a zinc-finger nuclease (ZFN) to render the CCR5 gene permanently dysfunctional in the T-cells taken from the patients, and then transfused the cells (about 10 billion of them) back into the patients.
They report that 11-28% of the T-cells were modified by the ZFN. The mean half life of the treated T-cells was 48 weeks, which was longer than for untreated T-cells. While this was primarily a safety and proof of concept study, they did follow some HIV parameters, and report:
“HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.”
Again – this is a preliminary study, not a definitive clinical trial. If all goes well it will still take years to develop this technique as a treatment. Also, as is, this is not a cure, but rather another weapon against HIV. It will also be a highly expensive treatment.
The hope is that with this treatment patients with HIV may be able to forgo medications for several years. This will offset the cost of the treatment, and may even make it cost effective. Perhaps combined with medication it may also reduce viral loads more quickly and thoroughly in the early stages of treatment, further reducing morbidity of the disease.
What’s most exciting to me is that this is an entirely new approach to HIV instead of using drugs. The researchers essentially altered the gene function in the T-cells of the patients in order to make those T-cells resistant to HIV. It is also an important proof of concept in terms of the role of the CCR5 receptor, although this has also been demonstrated by previous research.
This suggests the plausibility of using gene therapy to treat HIV. The technology of altering the genes of a human subject has proven, unfortunately, very challenging. Significant safety issues remain, keeping the treatment experimental for now. If, however, we can overcome the safety issues (such as runaway viral infections caused by the viral vectors used to transplant the genes), a world of options opens up.
One of those options could be transplanting variant genes for CCR5 that are resistant to HIV infection, essentially rendering subjects immune to HIV.
It’s exciting to talk about the potential of future technology, but also always highly speculative. Twenty years ago we thought we were on the brink of gene therapy, and there was the general sense that we would have been much further along by now, but reality proved more challenging. There is also the general tendency to overestimate short term scientific advance (benefits of the genome project, stem cell therapy, brain-machine interface, and gene therapy, for example). But also there is the tendency to underestimate long term progress. It may take 20 years longer than we thought, but the eventual benefits of such technologies may end up exceeding expectations. What we can’t predict is which technologies will pan out, and which ones will stall or turn into dead ends.
There is another recent science news item relating to HIV that is quite exciting. About a year ago it was reported that a child born with HIV from her mother was HIV free after receiving high dose anti-retroviral medication shortly after birth. This was presented as a cure of HIV (reasonably so). Now the same researcher reports the apparent cure of a second child with the same technique, high dose medication administered shortly after birth. The technique still needs to be researched for safety and efficacy, but if it pans out it may become routine to cure infants born with HIV.
One of the challenges of being a science communicator is balancing enthusiasm and the “gee-whiz” excitement of new scientific developments, with a cold and sober assessment of the current limitations of what we know and what we can do. This is the “cautious exuberance” approach applied to science reporting. We want people to be excited by science, but to also know where the line is between science and science fiction.
In the case of HIV science and treatment, however, I think the public does not generally appreciate how much of a science success story this is. This is a case where advances exceeded our cautious predictions. I would not have thought earlier in my medical career that at this time patients with HIV would have essentially a normal life expectancy and that we would be dabbling with outright cures.
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