Deciphering Immunology’s Dirty Secret

Before Bali Pulendran started his first major protocol at the Emory Vaccine Center in Atlanta, he wanted to meet his subjects. So, in the fall of 2004 he and postdoc Marcin Kwissa drove the 25 miles to Lawrenceville, Georgia, and the Yerkes Primate Research Center’s field station. There, Pulendran and Kwissa stood face to face with their trial participants: 25 rhesus macaques. “I remember staring at them and thinking: ‘Wow, these are who we’re going to be vaccinating’,” says Pulendran.

Nearly two years have passed and those monkeys now reside in the next building over from Pulendran’s office, where they’ve entered the final phases of a clinical trial for an HIV DNA vaccine developed at the center. The vaccine has already successfully reduced viral load in nonhuman primates, and it’s being tested in humans. Pulendran is adding a new twist, however. Two groups of the immunized monkeys have also received an adjuvant that targets toll-like receptors (TLRs), key components of the innate immune system.

HIV vaccine strategies have been vexed by, among other things, the virus’s ability to disarm the immune system and the immune system’s inability to generate antibodies against the virus. But discoveries just in the past decade have uncovered a wellspring of innate immune targets that appear to converse with the adaptive response and may aid in shutting down HIV. “By giving a TLR ligand with the DNA vaccine, can you make the immune response stronger and get an even more profound effect on the viral load?” he asks. The strategy is young, and at 40 years old, so is Pulendran.

In August 2006, the 25 monkeys were brought to the Atlanta campus to be infected with SIV, and the excitement is palpable. The true test will be whether the subjects that received TLR adjuvants have significantly reduced viral loads. Pulendran has been awaiting the results from the virology lab for weeks. “I’m hopeful,” he says, pausing and then drawing in a deep breath. “But we’ll see.”

Read the entire story, Deciphering Immunology’s Dirty Secret, in The Scientist.

Eat Your Way to Better DNA

Published in The Scientist, September 2006:

Jose M. Ordovas has been studying the role of lipoproteins in heart disease for decades. His laboratory and others have tried to tease out how these proteins factor into why some people

Credit: RICK CONTRERAS

can eat an unhealthy diet – that is, lots of dietary fat – and still have high levels of what is often referred to as good high-density lipoprotein (HDL) cholesterol. The senior scientist and director of the Nutrition and Genomics Laboratory at Tufts University in Boston honed in on APOA1, which encodes the HDL component apolipoprotein (apo) A-I. A specific SNP in its promoter region (APOA1 – 75G/A) was first identified in the early 1980s, and studies in the decade followin scrutinized the association between the G and A alleles and HDL concentrations. The results varied widely. Some studies suggested that carriers of the A allele (about 25% of the population) had higher HDL levels than carriers of the more common G allele, but other studies came to the exact opposite conclusion.

In 2002, he and his colleagues tested whether dietary fat might modulate the effect of the allele. “We decided to consider whether APOA1 is regulated by nutrients, since people are eating different things,” Ordovas recalls. They looked at 755 men and 822 women who were participants in the Framingham Offspring Study, a population for which there are rigorous data on HDL levels, other cardiovascular risk factors, and dietary fat intake. They paired this information with genotype data for each patient and found that the polymorphism on its own didn’t have an effect on HDL level. Instead, in people heterozygous or homozygous for the A allele, “what we found is that polyunsaturated fatty acids, which are very good regulators of gene expression, happen to modulate the expression of this genotype,” Ordovas says.

It was the sort of finding that laid the foundation for the nascent field of nutrigenomics. At its core, the field is the study of how genes and nutrients interact to promote health or disease. It also includes understanding how gene and protein expression are affected by the presence or absence of specific nutrients, whether and how diet-regulated genes play a role in disease, the degree to which an individual’s diet affects the risk of disease given his or her genetics, and whether one’s diet may be altered to maintain that balance between health and disease.