Q&A: A New Test For Drug-Resistant HIV Breaks All the Scientific Rules

[Winter 2016]

A former postdoctoral fellow with the Harvard T.H. Chan School of Public Health AIDS Initiative, virologist Iain MacLeod in 2014 cofounded Aldatu Biosciences, which provides sensitive and cost-effective diagnostics to detect drug resistance in antiretroviral treatments for HIV. The first drug-resistance test designed specifically for use in Africa, it can be stored at room temperature and provides results in two hours—compared with current methods that require refrigeration and take two to three days. In 2014, Aldatu Biosciences won the Harvard University’s Deans’ Health and Life Sciences Challenge and was later awarded $1.5 million by the National Institutes of Health to develop its diagnostic method. MacLeod spoke recently with Harvard Public Health editor Madeline Drexler.


Q: What can your product do that current tests for HIV drug resistance cannot?

A: Think of the HIV genome as a lock for which you’re given two keys. One of the keys works when there is drug resistance, and the other key works when there is no drug resistance. The problem is that with HIV, the lock is always changing. What our test does is essentially pick the lock and give you a master key that can rapidly determine whether the virus is drug-resistant.

Q: How exactly does it work?

A: We strip out all of the secondary, non-resistance mutations in HIV—we actually change the HIV genome to match the test. Then we can sensitively detect the single nucleotide changes associated with resistance.

Our test is based on a technology known as PANDAA, for Pan-Degenerate Amplification and Adaptation. It’s a new way of doing a very old and very common molecular biology technique known as real-time polymerase chain reaction, or qPCR, which is the mainstay of modern genomics. Researchers use qPCR to amplify genetic sequences in a sample so that they can tell whether a particular pathogen is present. One of qPCR’s benefits is that it’s highly sensitive—it can detect a single nucleotide or base pair change within the gene of a pathogen or a human cancer. But that sensitivity falls flat when there are other mutations around, such as in a highly mutable virus like HIV.

Q: You turned a familiar technology inside out.

A: Yes. Even now, half of the scientific community doesn’t believe that our test works.

Q: Why are they skeptical?

A: Because we intentionally violated every single design principle for qPCR. Everything we’re doing goes against more than a quarter century of rules that don’t take into account subsequent scientific developments. PANDAA takes all these advances and bundles them together.

The problem today is that researchers have been too busy looking for big data and big genomic answers. Traditional HIV drug-resistance testing uses standard DNA and RNA sequencing. You get information for huge regions of the genome, but only about 1 percent of that information is clinically informative.

We call PANDAA “focused genotyping.” It’s designed to get resistance infor- mation for six different discrete positions on the HIV genome—the six mutations that confer drug resistance in patients starting World Health Organization (WHO)-recommended first-line therapy. One or more of these mutations will be present in at least 99 percent of people failing first-line treatment in Africa. Information on the other 1,200 genetic mutations you won’t get, because you don’t need it.

Q: As you roll out this test, who are your target populations and what are your main scientific questions?

A: Aldatu’s initial target will be first-line failures of the entire adult population
in Botswana receiving antiretroviral therapy. With a health economist at Harvard Chan, we will gather real-world metrics on the impact of resistance testing on the health care system.

And with Christopher Rowley, a research associate at Harvard Chan, we’re going to do pretreatment resistance testing for pregnant women in Botswana, because they were actually the population that inspired PANDAA’s development. When a Botswana Harvard AIDS Institute study started in 2010, about 4 percent of women who were coming into antenatal clinics had resistance. It’s now up to 10 percent. We’re talking about one in 10 women who have been put on drugs to prevent mother-to-child transmission—and the drugs are probably not going to work. We hope to follow the pregnant women who are tested and, if they have resistance, are switched to the correct antiretroviral drugs, to see whether they are less likely to transmit HIV to their infants.

Q: This past fall, the WHO issued guidelines to immediately start drug treatment for anyone diagnosed with HIV—potentially, nearly 40 million people globally. How will this affect drug resistance?

A: I think the new guidelines are the best approach for stemming the spread of the epidemic, but I also think it’s foolhardy not to put in place the correct diagnostics for drug resistance. There is no single mention of the word “resistance” in their plan to get everyone on treatment and virologically suppressed. You’re putting people on drugs because politically it sounds great. But at the end of the day, you’re not doing anyone any good if the drugs aren’t working. Year on year, both transmitted and acquired resistance to HIV antiretrovirals is increasing worldwide.

Q: You and cofounder David Raiser named your company Aldatu, which is a Basque word. What does it mean?

A: Dave and I didn’t want to go with a science-sounding name, because everyone does that. So we looked at words that meant “adapt,” because what PANDAA does is adapt qPCR for HIV drug-resistance testing. “Aldatu” not only means “change” but also, in a more poetic translation, “to become something different.” Creating a startup company was never in my five-year plan. I was going to be an academic scientist, and Dave was going to be a management consultant. The word “Aldatu” refers to the novel technology, what it does to the HIV genome when we’re running the test—and how this whole experience has changed us.

— Madeline Drexler

Photo:  Kent Dayton/ Harvard Chan School