Traditionally, biologists have interrogated narrow avenues of information, learning, for example, what a T cell does without the ability to measure its interactions. “Systems biology lets you measure everything,” says Rafik-Pierre Sekaly, Ph.D., scientific director at the Vaccine and Gene Institute. By taking such a systems approach, “you find novel things you never thought to ask.”
That approach led him to the understanding that, in HIV, T cells are dysfunctional. Based on this understanding, Argos Therapeutics has invented and developed an HIV vaccine that is in Phase II trials now, and Dr. Sekaly’s lab is participating in and analyzing immuno-monitoring data from this trial.
Basically, Argos’ therapy re-educates a patient’s immune system. The therapy is designed by extracting dendritic cells from a patient, introducing them to that patient’s own HIV virus, and then reintroducing these dendritic cells back into the patient, enabling the immune system to respond more robustly.
Phase II trials of the Argos vaccine are showing a viral load reduction that is so significant that some of the patients have stopped their drug regimen for up to six months without increasing the viral load, Dr. Sekaly says.
The next step, he adds, is to introduce the knowledge of systems biology to develop better adjuvants.
Paul de Bakker, Ph.D., assistant professor, Brigham and Women’s Hospital and Harvard Medical School, and associate member at The Broad Institute, is studying the host genetic basis of spontaneous control of HIV. Specifically, he is looking for genetic variations between HIV elite controllers and HIV progressors to determine why the disease does not advance substantially in elite controllers or viremic controllers (those whose HIV viral loads are, respectively, below 50 virus particles or between 50 and 2,000 virus particles, per milliliter of blood). To put that in perspective, the viral load for untreated patients averages more than one million particles at the time of acute infection.
This work is being done in collaboration with Bruce Walker, M.D., professor of medicine at Harvard Medical School and director of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, under a grant from the Bill and Melinda Gates Foundation. As a result of this work, “we are now able to explain associations of HLA alleles that have been documented for many years,” Dr. de Bakker says.
“We have developed a novel computational approach to look at specific amino acids in molecules of the immune system. Something is happening on chromosome 6. There’s a lot of variation, so it is difficult to read the genome in terms of what is important for elite controllers and what is not. Evolution has left a wicked mark on this part of the genome.”
Dr. de Bakker’s lab is looking closely at HLA genes, which are important in determining how the immune system reacts to nonself entities it encounters. “We are looking at proteins encoded by these genes to pinpoint specific amino acids that can at least partially explain why some are controlling the virus and why others are not.”
His lab uses Illumina microarrays installed at the Broad Institute to interrogate up to one million SNPs. The limitation to that approach is the number of samples needed to unequivocally determine which genes are causal factors in the replication of a specific, complex viruses like HIV. That is exacerbated by the relatively small population of elite controllers. To date, this project has included approximately 1,000 controllers and 3,000 noncontrollers. “These numbers pale in comparison to the numbers of patients investigated in other diseases,” Dr. de Bakker says.
“We’re getting some pretty exciting results so far. The next question is how to use this information to build a more complete picture of how viral peptides are presented to the immune system.”
These and other concepts in systems biology will be explored more fully at the the Institute for Systems Biology’s “Systems Biology and Global Health” conference next month in Seattle.