Dendritic-cell treatment boosts therapeutic vaccine prospects

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A group of French and Brazilian researchers have claimed a possible success in boosting immune responses and controlling HIV in a clinical trial where 18 people were treated with a vaccine prepared from their own virus. While these results are encouraging, this is only a preliminary report of a trial with no control group and the procedure could be difficult to scale up for widespread use.

Cells called monocytes were extracted from volunteers’ blood, grown in laboratory conditions and transformed into dendritic cells, which alert the immune system to possible infections. These dendritic cells were loaded with a chemically-inactivated preparation of HIV taken from the same person, and then transfused back into the trial volunteer.

All 18 Brazilian volunteers – 16 women and two men - had stable viral loads of at least 10,000 copies/ml for at least six months before treatment, had mean CD4 counts above 400 cells/mm3 (range 270-1009) when treated and were not on antiviral drugs - although three had been treated during pregnancy to prevent mother-to-child transmission.

Glossary

antiviral

A drug that acts against a virus or viruses.

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

statistical significance

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are ‘statistically significant’. 

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

immune system

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

In eight out of the 18, viral load fell by more than 90% (a one-log reduction) when measured one year after treatment, along with stable or rising CD4 counts. The other 10 also had reductions in viral load, but these were not sustained. Across the whole group, there was a statistically significant reduction of viral load over the course of the year and an increase in CD4 counts of around 100 cells/mm3 which returned over one year to baseline values. This contrasted with the six months before treatment, in which CD4 counts fell by an average of 100 cells.

The researchers looked for a variety of HIV-specific immune responses. There was little or no evidence for antibody responses, but increased levels of HIV-specific CD4 T-cells and of HIV-specific perforin-expressing CD8 cells (i.e. those which are most capable of destroying other cells) went with reduced viral load. There were no adverse effects reported, and no minor infections or other clinical symptoms, though some lymph-node enlargement was detected.

One of the lead investigators, Dr Jean-Marie Andrieu, has estimated that the cost of the therapy could be $4,000 to $8,000 per patient, which compares favourably with the current cost of a year’s antiviral drugs, at least in Europe and North America. People with CD4 counts at these levels would not normally receive antiviral drugs, but if this treatment could defer the need for medication, monitoring and hospitalisation - and especially if it could be repeated - it might be cost-saving. The advantage of a one-off or annual treatment without adherence problems is also obvious.

Another possibility, raised by the researchers, is to reduce onward transmission of HIV by treating people who would not qualify for antiviral drug treatment. All 18 volunteers in this trial had viral loads above 10,000 copies before treatment. One year later, four of them had less than 1500 copies. In a well-known Ugandan study of heterosexual couples, individuals who had viral loads below 1500 copies did not appear to transmit the virus to their partners.

However, it would be essential to repeat and extend this trial with a proper control group in case selection bias or the effect of close clinical monitoring has contributed to the positive outcomes reported here. There must also be a question about how far this approach could be scaled up and reduced in cost, to be made available in settings where laboratories currently struggle to provide even the most basic immunological tests. Scaling up drug production is one thing, but large-scale systems to isolate and process live HIV, which will always require high level lab facilities and advanced training, is quite another.

References

Lu W et al. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nature Medicine online publication doi:10.1038/nm1147, 28 November 2004.

Viral load critical in heterosexual transmission