Wednesday morning Harvard AIDS researcher Bruce Walker called one of his long-time patients with an announcement: "We've found the needle in the haystack!"
Actually, Walker and his colleagues have found a half-dozen needles. They pinpointed genetic variations that change amino acid building blocks in key proteins in the immune system. These differences help explain why some patients can be infected with HIV for decades, never get treatment and yet never progress to AIDS.
"We've found the five or six amino acids that explain the difference between people doing well or doing badly," Walker says.
The discovery is being published online by the journal Science.
The patient Walker called Wednesday morning is a 54-year-old Episcopalian priest named Robert Massie who's a fellow at Harvard's Kennedy School of Government. Massie inspired Walker's 17-year search for the secret of these HIV controllers.
Massie got infected with HIV way back in 1978 – several years before AIDS was recognized — from the constant injections of Factor VIII clotting factor he needed to treat his hemophilia.
Hemophiliacs were a bellwether group that helped scientists zero in on the AIDS virus. Many of them got infected early in the pandemic because Factor VIII was made from the blood of hundreds of donors. If even one was carrying HIV, the clotting concentrate was an efficient way to transmit the virus to unsuspecting hemophiliacs.
It turns out that the half-dozen amino acid variants that have protected Massie against AIDS are the same ones the Harvard-led team has found in others of European descent, those of African descent and Hispanics.
With the discovery, a number of other findings are falling neatly into place.
For instance, scientists have previously shown that people whose immune systems can control HIV are more likely to have certain "flavors" of an important immune trait called HLA (for Human Leukocyte Antigen). The HLA system allows the body to distinguish between its own healthy cells and those infected by foreign invaders, such as viruses.
But until now, scientists didn't know what it was about the more favorable HLA subtypes that conferred protection against HIV.
The genetic instructions for the newly found amino acid variants resides in a region of chromosome 6 that codes for the HLA system. Five of the six variants are within a protein that controls how certain immune cells, called CD4s, display bits and pieces of viral protein on their outer shell – if they happen to be infected with a virus. HIV has a special affinity for infecting CD4 cells, and without constant antiviral treatment the virus slowly destroys the immune systems of most infected people.
But if a person has the newly discovered amino acid variants, his CD4 cells will be especially good at displaying pieces of HIV in a binding groove, or pocket of their outer coat. That enables killer cells, immune cells called CD8s, to target and kill the infected cells before they can spew forth more viruses.
For most people, the lack of these protective variants renders their HIV-infected cells invisible to their immune system.
"What we know for absolute certain is that these variants alter the way the viral protein sits in the binding groove," Walker says. "Now we're working on exactly how the protein is presented to induce a protective immune response.
"The exciting part of this finding," he continues, "is that it helps us focus on something that clearly is important and hopefully will allow us to manipulate the immune response" of people without the protective trait.
Walker acknowledges that "we have a long ways to go before we can turn this finding into something that will prevent someone from becoming infected with HIV or augment their immunity. But this takes us a step closer to defining and effective immune response."
Vaccines are one way to manipulate the immune response. But nobody has ever used a vaccine in such a targeted way.
Massie says he was "very, very happy" to hear of the discovery. "I know they've devoted a huge amount of time, money, effort and emotion to try and unlock this puzzle," he says.
Meanwhile, Massie is keenly aware of his own good fortune – and not only at being born with the genetic talismans that have protected him from HIV.
He wasn't protected, it turns out, against hepatitis C, also acquired from injections of Factor VIII concentrate. Hep-C destroyed his liver.
A year ago, he had a liver transplant. And, there's a silver lining: The transplant has cured his hemophilia, because his new liver can make the Factor VIII he needs to prevent bleeding.
"I used to have four or five injections a day to maintain the right level of Factor VIII in my blood, " Massie says. "All that's behind me."