Now that some people have been living with the human immunodeficiency virus (HIV) for decades, a unique phenomenon is emerging: patients who have not progressed to acquired immune deficiency syndrome (AIDS). These so-called “elite controllers” manage to not only keep the virus so low it is virtually undetectable in their bloodstream, but to do so without the use of antiretroviral medications, standard therapy for HIV patients.
Researchers are studying elite controllers, including those with hemophilia who contracted HIV through contaminated blood in the 1970s and 1980s, to determine what’s different about their genetic makeup and immune systems. Pinpointing the mechanisms at work in these patients could lead the way to the development of better drugs and perhaps a vaccine one day.
To understand the research under way on elite controllers, one first has to understand the inner workings of the immune system.
Immune System 101
Immunity to foreign invaders, or antigens, is coordinated by a sophisticated surveillance system. Coordination among many types of cells ensures the detection, capture and destruction of antigens such as bacteria, parasites and viruses. When an antigen tries to enter the body, antigen-presenting cells attach to it and present it to T cells, specialized lymphocytes (white blood cells) with different functions. The CD4+, or helper, T cells initiate and oversee the body’s response to infection. The CD8+, or killer, T cells produce antibodies that fight cancers and viruses.
The antigen-antibody relationship is often described as a lock-and-key system. When the antibody, or key, is in the antigen, or lock, the antigen cannot reproduce. The T cells then travel to the site where they multiply, attach to the antigen and destroy it.
How HIV Handicaps the Immune System
Most viruses attack an organ in the body. For example, hepatitis viruses infect the liver, and rhinoviruses penetrate the nasal cavity. But HIV attacks the immune system, the body’s defense against viruses themselves. It co-opts its host’s CD4+ T cells by attaching to them and infecting them with the virus. At first, the immune system produces more CD4+ cells to replace the damaged ones. But over time, demand exceeds supply. The immune system fails to produce enough CD4+ cells, allowing the HIV to proliferate uncontrollably.
The CD4+ cells play a regulatory role for the entire immune system. “If the regulator is not there—and one that is critical for fighting off viruses—the patient is at greater risk for immune compromise, meaning that you can’t fight infections successfully,” says Margaret Ragni, MD, MPH, professor of medicine at the University of Pittsburgh and director of the Hemophilia Center of Western Pennsylvania. The weakened immune system is then susceptible to opportunistic infections from bacteria, fungi, viruses and other microorganisms. “Those are the infections an intact immune system would be able to keep at bay.”
Two tests that measure the progression of HIV are CD4+ cell count and viral load. A normal CD4+ cell count ranges from 600 to 1,200 cells per cubic milliliter (ml) of blood. Therapy with antiretroviral drugs is usually begun in patients whose CD4+ cell counts have dropped to 200–500 cells/cubic ml. When the T-cell count is fewer than 200 cells/cubic ml and an opportunistic infection sets in, the patient is diagnosed with AIDS.
The viral load test measures the number of copies of HIV in one milliliter of blood. The higher the count, the more likely the patient is to progress to AIDS and transmit the virus to others. The average untreated patient has a viral load of 10,000 to 1 million copies of the virus during acute infection, according to the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health.
The goal of antiretroviral therapy is to decrease the viral load to undetectable levels; using today’s technology, that means fewer than 50 copies of HIV/ml of blood. However, an undetectable viral load in the blood still means that patients have HIV and can transmit it. Approximately 2% of the virus is found in blood; the rest is in body tissues, such as the brain, lymph nodes and spleen.
Mining the Mechanisms of Elite Controllers
Elite controllers are defined as having fewer than 50 copies of HIV/ml in their blood for at least one year without medication. An estimated one in 300 HIV patients is an elite controller.
The International HIV Controllers Study, based at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard in Charlestown, Massachusetts, is recruiting US and international patients for its multisite study. So far, 1,500 people have enrolled: 500 elite controllers and 1,000 viremic controllers, those with fewer than 2,000 copies of HIV/ml of blood. The average time of infection of the subjects is 12–14 years; the longest is three decades. “If we could figure out how people achieve a really low viral load and re-create that in other people, we would expect that the epidemic would rapidly contract,” says Bruce Walker, MD, director of the institute and principal investigator of the study. He is also professor of medicine at Harvard.
Investigators are scanning patients’ genomes, or genetic makeup. Of the 3 billion nucleotides in the human genome, they have found a handful that help explain which patients control HIV. “We essentially found five amino acids that accounted for the genetic determinant of viral load,” Walker says.
Those five amino acids belong to the human leukocyte antigen (HLA) complex, which helps the immune system differentiate its own proteins from foreign proteins. When HIV invades a cell, it redirects the cell’s machinery to produce HIV. In patients who can’t control the virus, HIV keeps cranking out more copies of itself. However, in elite controllers, a different scenario occurs. “Think of HLA as a factory worker who grabs a piece of the virus protein, hangs it out the cell surface and tells the immune system to kill the cell,” says Walker.
That early warning system makes all the difference in the effectiveness of killer T cells being activated and destroying the virus early, before it hijacks the entire factory. In a 2008 study in Immunity, NIAID researchers, led by Stephen Migueles, MD, discovered a sizable discrepancy in the ability of killer T cells to disable HIV. Elite controllers’ killer T cells destroyed 68% of infected cells in an hour versus 8.1% for noncontrollers. They do it by producing more of two important proteins: perforin and granzyme B. The tag team works together to destroy HIV. First the perforin creates a pore in the HIV’s membrane, which then allows granzyme B to enter HIV and program it to self-destruct.
Other NIAID researchers have discovered that the killer T cells of elite controllers have polyfunctionality, the ability to create and disseminate chemical messengers in greater numbers and with more variety. These traits are important in helping the immune system fight a host of viral infections, including HIV.
Further, the killer T cells in elite controllers are more broadly reactive than in noncontrollers, able to recognize even small mutations in the virus. These findings came from a 2010 study in Nature that Walker co-authored. “What we’re trying to learn from this is exactly how one can induce the most functional T cells,” he says.
Another group of researchers at the Ragon Institute, led by Mathias Lichterfeld, MD, has identified yet another mechanism at work in elite controllers, the P21 protein. The results of their study, published in the April 2011 issue of the Journal of Clinical Investigation, showed that P21, a tumor-suppressing protein, blocked HIV at two stages of its life cycle within CD4+ T cells. In addition, levels of the protein were 10 to 20 times higher in the CD4+ T cells of elite controllers. When P21 was experimentally inactivated in CD4+ T cells taken from elite controllers, HIV replication increased.
An alternate method of inhibiting HIV infection is to block its ability to attach to cells. Researchers at the University of Texas Medical School in Houston reported at the 2008 International AIDS Conference in Mexico City that some patients produced antibodies to HIV that prevented it from gaining a foothold in the first place. One group of patients in the study were long-term nonprogressors, HIV patients with a higher viral load than elite controllers, but who had not progressed to AIDS after many years. The investigators, led by Sudhir Paul, PhD, professor and director of the chemical immunology research center at the Houston medical school, discovered that this group produced antibodies against gp120, a glycoprotein on the surface of the HIV envelope that helps the virus stick to the hosts’ T cells. (See “Powerful Antibodies Prevent HIV’s Attachment,” HemAware January 2009.)
Future Vaccine Development
HIV is notorious for mutating quickly, avoiding detection by the immune system. That changeability and the fact that it is not one virus, but perhaps tens of thousands, have prevented the development of effective vaccines.
However, elite controllers may reveal the right path to take to create a lasting vaccine. “What we discovered is that the mutations that are being induced by the immune systems of elite controllers are impairing HIV’s ability to replicate,” says Walker. Those mutations make the virus less fit, he says. “It has to struggle more to make copies of itself.” This mechanism and others may help researchers develop a vaccine that controls symptoms and lowers the risk of transmission of HIV.
“One of the things that separates us all as individuals with hemophilia is that our genotype, or genetic mutation, is different for each patient or family group,” says Val D. Bias, CEO of the National Hemophilia Foundation. (See “What’s Your Genotype?” HemAware Spring 2010.) He encourages elite controllers to enroll in clinical trials. “We need to know why people are able to control their HIV if they’re not on any kind of drug regimen.”
“This is a phenomenal international resource to have these patients and to be able to try to understand the workings of an effective immune response,” Walker says.