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elite controller research

UCSF Researchers Study Elite Controllers
So Much Promise Requires Risky Research

By Sandra Spence

“You’re going to learn the most from people who survive an infection.” That’s what Jay Levy’s mentors told him as he trained in virology long before he co-discovered HIV in 1983. Within in a year of that discovery, an HIV/AIDS “survivor” walked through the door of Levy’s clinic at the University of California, San Francisco (UCSF).

“He was perfectly healthy,” recalls Levy, head of the Laboratory for Tumor and AIDS Virus Research at UCSF. “He showed no symptoms, and we found he was infected. This was the first time that anyone had an inkling that there could be people who were walking around with HIV and not be sick. We have been following this man since 1984.”

Putting a Definition on “Survivor”

Survivors. Long-term non-progressors. HIV controllers. Elite controllers. These are some of the names given to HIV-infected men and women who manage to control the virus’s invasion into their bodies. Without the help of any drugs, they somehow keep the virus from replicating uncontrollably and prevent the virus’s lethal damage to their immune system. What is the secret of these individuals? What can we learn from them? Can they point researchers in the direction of a cure for AIDS? These are just a few of the questions that physician scientists at UCSF and San Francisco General Hospital (SFGH) are trying to answer.

According to HIV/AIDS researchers like Levy and Steven Deeks, a professor in the Department of Medicine at UCSF and faculty member of the Positive Health Program at SFGH, “long-term survivors,” or “non-progressors,” make up about 5 to 15 percent of HIV-infected individuals. These people manage to maintain very low or even undetectable amounts of HIV in their blood and remain healthy without the dramatic loss of CD4+ T cells characteristic of most patients with HIV infection. “Elite controllers” represent a special subset of this group, having HIV levels undetectable by standard viral load tests, without the use of antiretroviral drugs. Probably fewer than one in a hundred individuals infected with HIV meet this standard.

San Francisco has proven to have benefits when it comes to studying long-term HIV survivors and elite controllers. Foremost, it has been possible to find relatively large numbers of these individuals. At San Francisco General, a concerted effort to recruit these rare subjects begun in 2005 has resulted in a group of at least 200 individuals having very low viral loads, of which approximately 80 meet the strict definition for elite controllers.

Part of the team’s success in finding these individuals is due to the maturity of the HIV epidemic in the San Francisco Bay Area. Though viral load testing is relatively new, many of the patients who show consistent control of the virus with no apparent symptoms have been followed since their initial HIV infection in the 1980s. They are the living proof that this typically virulent and aggressive virus can be held at bay for decades, and they provide hope that it might be stopped completely.

Survivor Advantage: Virus or Host?

The answers that elite controllers can offer might seem elementary, yet the complexity of HIV’s interaction with the human immune system makes them far from easy to unlock. Controllers’ apparent anti-HIV immunity is clear; how they achieve it is not.

Do elite controllers survive because they have been infected with defective HIV mutants that attack their human hosts weakly, or do these human hosts, the HIV controllers, have something special about their immune systems that helps them fight HIV better?

The question about defective HIV mutants is still an open one, but Levy and Deeks agree that a weak virus alone does not explain the remarkable survival of all elite controllers. “At the end of the day,” says Deeks, “I suspect that a subset of these people has been infected with a replication-incompetent virus. But, for the most part, when you can find the virus in controllers, it replicates quite well.”

Jay Levy (left) studies the immune system of non-progressors, people with HIV infection who never develop AIDS, such as Erik von Muller (right).

The Secret Weapon of the Elite Controller Immune System

So, if there is something extraordinary about their immune systems that makes elite controllers nearly impervious to HIV, what exactly is it? At the Parnassus Campus of UCSF, Dr. Levy and others in his lab have been relentless in the pursuit of an elusive antiviral factor secreted by CD8+ lymphocytes. Those particular white blood cells are components of the innate immune system, the first line of immune defense that responds quickly and non-specifically to infective intruders.

In the small office where each month Levy draws blood samples from long-term survivors, he explained why his focus became locked on CD8+ cells and the factor they produce. In 1986 Levy and his co-researchers found that when HIV-infected CD4+ cells were placed, in culture, in the presence of CD8+ cells from long-term survivors, they stopped producing HIV. When the CD8+ cells were removed, HIV production resumed.

Pointing to a long list of compounds in his recently published textbook, HIV and the Pathogenesis of AIDS, Levy says, “We spent six years trying to figure out what it wasn’t. Then we have spent the last ten years trying to figure out what the CD8+ antiviral factor is. It is the only other natural antiviral substance besides interferon. We can’t find it because it is produced in such small amounts by the CD8+ lymphocytes.”

Unlocking the identity of this CD8+ antiviral factor (CAF) is a difficult process. Levy uses a multipronged approach involving low-abundance protein chemistry techniques to purify potential CAF candidates, cell biology techniques to assay the candidates, and DNA microarrays to identifying which genes or combination of genes control CAF production.

Levy’s work on CD8+ cells led him to another component of the frontline, innate immune system, plasmacytoid dendritic cells (PDCs). They not only produce interferon when challenged by viruses, but also interact to enhance the activity of CD8+ T cells. Long-term survivors have higher-than-average PDC counts, and elite controllers, higher still. Finding the mechanism by which they are triggered to release interferon is a second key focus of the Levy laboratory.

But could long-term survivors have other ways to suppress HIV? Over at Ward 84 at SFGH, Deeks, who recently co-authored a comprehensive review of research into mechanisms of virus control implicated by HIV controllers,1 pauses to perform a quick mental inventory. “I’d say that there are probably 20 to 30 known, possible, or theoretical mechanisms of control. I would put it in that ballpark. Some have been tested, some have not.”

And, he adds another dimension of intricacy to the picture. “The key issue is that probably no one factor will be sufficient. So, it is likely a complex situation in which elite controllers have one, two, or three things that help them control the virus. And they have different mixtures.”

A daunting puzzle, yes. Impossible to solve? According to Deeks, probably not. With a 15-year career entwining clinical care and research into HIV/AIDS, he speaks with an optimism rooted in a long-term perspective. “I started at San Francisco General Hospital in July 1993, an interesting month. It was the month that data emerged that AZT—which we had previously thought was a good drug—turned out to really not have any long-term effect whatsoever. That’s when people were dying right and left. Hope was gone. So, when you look at the history of the epidemic, that was the absolute low point. And, since then, it has dramatically gotten better.”

Dr. Steven Deeks, a professor in the Department of Medicine at UCSF and faculty member of the Positive Health Program at SFGH, studies elite controllers.

Studying his cohort of elite controllers, in collaboration with others, Deeks has looked at genetic and functional characteristics of the T-lymphocyte response to HIV infection. They chose to focus on this arm of the immune system first, as it is well known that the so-called “adaptive” T cell immune response is the primary mechanism that humans use to prevent or control chronic infections. Although many elite controllers had clear evidence of potent HIV-specific T cell immunity, a surprising number failed to exhibit such a response. This unexpected result suggests that other, as yet undefined mechanisms may be responsible for the control of HIV in elite controllers. Given the recent, well-publicized failures of the T cell vaccine candidates to protect against HIV infection, there is now great interest in learning more about less well-studied mechanisms of viral control.

Like Levy, Deeks believes that components of the innate immune system show great potential to suppress HIV. So-called natural killer (NK) cells caught the attention of UCSF’s Douglas Nixon as well as Deeks and his collaborators in Boston and Philadelphia. They have found that the NK cells of elite controllers frequently express a unique cell surface protein or receptor that may regulate their function.

Deeks is also looking at why elite controllers have lower numbers of T regulatory cells compared to non-controllers. These cells act as a “brake” on the adaptive immune response, to prevent collateral damage to tissue caused by excessive inflammation and autoimmune attack. With fewer T regulatory cells, elite controllers ease up on the brake, holding back their T cell response to invading HIV. This activity may help them mount the kind of intense, powerful response required to stop HIV in its tracks.

Power in Numbers: The Need to Recruit More Elite Controllers

With so many mechanisms, and combinations of mechanisms, potentially at work in elite controllers, assimilating data from large numbers of them will be crucial to make statistically significant observations. That’s why Deeks is collaborating with Bruce Walker and Eric Lander of the Broad Institute at Massachusetts General Hospital in Boston and a host of other scientists, health-care providers, and AIDS service organizations to grow an international consortium. Their goal is to recruit 2000 elite controllers around the world.

Deeks points out another driving motivation to amass the largest possible cohort of elite controllers. Despite the many clues researchers have gleaned about how the human immune system battles HIV in both controllers and non-controllers, there may be key biological interactions yet to be uncovered. Deeks and his colleagues believe that in addition to pursuing solutions based on known biology, it is time to go on a massive “fishing expedition” within the entire genome of elite controllers rather than just pursue genetic differences correlated to currently suspected mechanisms.

To take stock of all significant genetic differences between elite controllers and non-controllers and then figure out what the genes related to those polymorphisms do represents the kind of high-risk, high-reward research that sets typical, hypothesis-based research on its head. DNA samples have been taken from more than 300 elite controllers enrolled in the international HIV controller consortium, and whole-genome scans have begun.

Real Challenges to Support Elite Controller Research

According to Deeks, there are three critical factors required to grow and support cohorts of elite controllers. First is the willingness of elite controllers to come forward and offer themselves to be studied. Both Deeks and Levy have found HIV controllers to be remarkably generous individuals, highly motivated men and women driven by a desire to give back to others with HIV/AIDS and to find answers to why they have been spared.

With a smile, Deeks describes their generosity. “They say, ‘Sure take my blood. Sure, do a gut biopsy. Sure, I’ll undergo a spinal tap.’ And we will only do what we think is important. But it is a big sacrifice on the part of these guys. A big sacrifice. They get nothing out of it. To do it for the good of science, that’s a pretty cool thing.”

Jay Levy (left) studies the immune system of non-progressors, people with HIV infection who never develop AIDS, such as Kai Brothers (right).

A second factor required for the study of elite controllers is active collaboration among researchers. Deeks also sees few barriers there. “[Scientific] competition, in general, is good. But for these types of issues, where there are multiple questions to be asked and there is a need for large cohorts, that just encourages collaboration,” he explains. “The elite controller approach is very conducive to collaboration. Funders are pushing us to do it. The promotion committees are now recognizing it. And people are just having more fun.”

Funding is the third essential ingredient, and, without a doubt, it presents the biggest challenge. First, there’s the price tag. “We need to find these individuals, bring them in, collect the tissues, collect the cells, collect the plasma, have them come back every four months, do all the genetic and viral load testing. It costs about $5,000 per person per year to really do that,” says Deeks. “We are talking about serious money, millions of dollars a year just to find these interesting people and then provide everyone in the world access to the cohort.” Then, there is the high-risk, shot-in-the-dark, innovative nature of some of the research to be done. “That’s just not the kind of research that the NIH has been funding.”

Lifetime HIV Control: A New Research Goal

For many HIV researchers, elite controllers hold such a gold mine of potential answers that supporting them as a platform for both novel and hypothesis-based research is an invaluable investment. And, given the failures of recent HIV vaccine trials, the time to begin taking risks on elite controller research is now.

Most significantly of all, research on elite controllers could open up an entirely new goal for HIV research, inspiring the new question, “Can we effectively cure people infected with AIDS?” rather than “Can we control or prevent the infection?”

“Elite controllers are not cured,” explains Deeks, “but they are as close to it as possible. We think of them as being like individuals who have had cancer and are in remission. So, we think of elite controllers as the reasonable goal for the treated population.”

A therapy or treatment strategy that enables HIV-infected individuals to remain healthy for decades without antiretroviral drugs—that objective is the true promise that elite controllers offer.

1 Steven G. Deeks and Bruce D. Walker, 2007, Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy. Immunity 27406–416.

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