One step closer to a cure for HIV/AIDS

How do you find a needle in a haystack? It takes a village.

The team at Duke Human Vaccine Institute (DHVI) has been working on a vaccine for HIV for four decades. After making the breakthrough discovery that the virus camouflages itself, the scientists have racked up numerous additional findings that have them on the cusp of an effective vaccine.

One of the ways that HIV outwits the immune system is by acting like a wolf in sheep’s clothing: It covers itself with sugar molecules, called glycans, just as normal human cells do. The disguise isn’t perfect, but it gives the virus a deadly head start on the immune system.

“By the time the immune system realizes the virus is an invader, it’s too late,” says Wilton Williams, director of the DHVI Viral Genetic Analysis Core Facility and associate professor of surgery. “The virus has spread to areas where the immune system can’t get to it.”

About 38 million people worldwide are living with AIDS, the disease caused by HIV. Pharmaceutical treatments can keep AIDS in check, but a vaccine has been elusive because of the complexity of the challenge.

Under one roof, we have a sequencing facility, we have a structural biology facility, we have immunologists doing basic science research. This collaboration helps the science move much faster and puts us in the space of doing innovative work. ”

Wilton Williams

Director, DHVI Viral Genetic Analysis Core Facility

HIV’s disguise, which scientists call the glycan shield, has one small patch that differs from the glycans on normal cells. Scientists have long wanted to target that area with a vaccine. The stumbling block has been the configuration of our antibodies, which are shaped like the letter Y. That shape keeps them from binding effectively to the glycans. It’s as if the key is the wrong shape for the lock.

DHVI scientists discovered a key that might work—a new class of antibodies that are shaped like the letter I instead of Y. The I-shaped antibody isn’t capable of neutralizing HIV immediately, but researchers believe it has the potential to evolve into an effective anti-HIV antibody with the encouragement of a series of vaccines.

Williams and the members of his lab looked at blood from uninfected people to determine the frequency of the I-shaped antibodies. Most people likely have them, but the I-shape is much less common than the Y-shape—it’s the proverbial needle in a haystack.

The discovery of the new class of antibodies was very much a team effort at DHVI. “Under one roof, we have a sequencing facility, we have a structural biology facility, we have immunologists doing basic science research,” says Williams. “This collaboration helps the science move much faster and puts us in the space of doing innovative work.”

Priyamvada Acharya, who directs the structural biology group at DHVI, uses the latest electron microscope to visualize antibodies with atomic-level precision. Without this technology, DHVI couldn’t have found the new antibodies or understood where and how they bind and what they interact with.

However, it’s not just the technology that made this discovery possible. “You have to know what you are looking for,” Acharya says. “That’s why people haven’t found these before.” The I-shaped antibodies are not stable and can change to Y-shaped and back, making the I-shape tricky to catch.

The team at DHVI is hard at work to develop a vaccine that can target the new antibodies and lead the immune system, step by step, to an immune response that can prevent HIV infection. Getting there will require continuous, intense, multidisciplinary collaboration, which has been an integral part of DHVI culture since its founding.

“Without the various parts [of DHVI] talking to each other every day,” Acharya says, “we wouldn’t have been able to make these discoveries, and we would not be able to move at this pace.”