In the mid 1990s, as the first wave of life-extending therapies for HIV began to reach the clinic, microbiologist Nathaniel “Ned” R. Landau, PhD, was puzzling over why some people infected with the virus never fell ill, even without medications, while others seemed immune to infection altogether. As a young scientist at the Aaron Diamond AIDS Research Center in New York City, he’d been studying how HIV slips into CD4 helper T cells—immune cells whose job is to rally other immune cells to fight off infections. It was clear that HIV grabs onto CD4 cells by attaching to a receptor protein on their surface, but that recognition was not enough. The virus needed another trick to fully infiltrate the cell.
The mystery went unsolved until 1996 when, in an unprecedented episode of academic confluence, Dr. Landau and his research partner, Dan R. Littman, MD, PhD, now the Helen L. and Martin S. Kimmel Professor of Molecular Immunology at NYU School of Medicine, announced the discovery of a second CD4 receptor, called CCR5, that also mediates HIV entry. The scientists tied five other labs in a nationwide race to publish their findings first, collectively confirming an ingenious two-step locking mechanism that permits HIV to ease its way inside the immune cells.
The discovery ignited a wave of excitement in the research world, but its clinical implications were even more stunning. Within months, Dr. Landau and another Aaron Diamond colleague, Richard Koup, MD, revealed that a mutation in the gene encoding the CCR5 coreceptor could confer immunity to HIV infection. Some of the patients who appeared immune to HIV, they found, were in fact missing the gene responsible for the CCR5 coreceptor. Remarkably, even people with only one copy of the defective gene had an edge over HIV: while they were still vulnerable to infection, they tended to stay healthier longer than those who did not have the mutation.
Disabling CCR5, it turns out, is not the only ticket to taking advantage of basic biological mechanisms to thwart HIV. “That discovery led to lots of research to try to understand whether other things can make people resistant to HIV infection and how the body fights against HIV in general,” Dr. Landau says.
Nearly three decades later, Dr. Landau, now a professor of microbiology at NYU School of Medicine, is zeroing in on a therapeutic vaccine he hopes will supercharge the immune system’s fighting force: the killer T cells that, once activated, can take down the virus. Indeed, a small number of people infected with HIV—fewer than 1 percent—do just that. For reasons still unclear, these so-called elite controllers are able to naturally suppress HIV replication. A vaccine that mimics this ability to hold HIV in check could effectively transform the 37 million people worldwide currently living with HIV into elite controllers.
“If we can develop a vaccine that will program an infected person’s immune system to act like that of an elite controller, so that they have a strong T cell response and suppress the virus, we might enable patients to come off their lifelong medications and be functionally cured,” says Dr. Landau.
Last year, in support of his innovative efforts, Dr. Landau received an Avant-Garde Award for HIV/AIDS research from the National Institute on Drug Abuse, part of the National Institutes of Health. The five-year grant, which provides $4.2 million in funding, will allow his team to expand testing of their therapeutic vaccine to nonhuman primates over the next couple of years.
The Limits of Antiretrovirals
Although the basis of a therapeutic vaccine involves mimicking the virus-suppressing skills of elite controllers, it’s not entirely clear how most elite suppressors themselves manage to keep HIV down. “That’s been one of the important questions in AIDS research for many years,” says Dr. Landau. Elite suppressors don’t harbor a weaker strain of HIV. “Their CD4 T cells are vulnerable to infection, as far as we can tell,” explains Dr. Landau. “They’re not intrinsically resistant, like people who lack CCR5.”
Instead, the killer T cells of elite suppressors—the immune cells that take cues from T cells to kill off infections—show a naturally vigorous response to HIV. “Perhaps they were previously exposed to something that caused a similar T cell response,” says Dr. Landau. “Or maybe it’s something in their genes. It’s not really understood. But what we do know is that these people exist. The virus never fully clears in these patients, but it remains controlled.”
By hindering viral replication, antiretroviral medications essentially do the same thing, and they have improved over the years. In the early days, “you had to take something like 15 pills a day, and they made you nauseated, depleted your bone marrow, and were very toxic,” Dr. Landau says. “Now, there are combination therapies that are as simple as one pill once a day, and overall, they are much better tolerated.”
Even so, each drug component comes with its own toxicity: some affect the kidneys; others, the bones. It’s not uncommon for patients to switch drug regimens due to side effects. Furthermore, taking one pill a day is not as foolproof as it sounds. If you miss a dose, the virus could develop resistance, which could then render a whole class of medications ineffective.
Globally, access to care remains a major challenge. “In the United States, we’re fortunate,” Dr. Landau says, “but there are many places throughout the world where medications and clinics aren’t readily available.” A therapeutic vaccine wouldn’t eliminate every single copy of the virus hidden in the body, but it would represent a functional cure. “It would be so much better than having to take a daily regimen of medications for the rest of your life and dealing with all of the side effects that can come with it,” says Dr. Landau.
A vaccine that prevents HIV infection continues to be a goal, albeit an elusive one. “There’s been a tremendous effort,” says Dr. Landau, “but it hasn’t worked so far.” A 2007 trial for a vaccine developed by the pharmaceutical company Merck, for example, was halted prematurely when volunteers who received the experimental treatment proved more susceptible to HIV infection than those who did not. “Whether a preventative vaccine will be possible remains to be seen,” says Dr. Landau.
A Louder Call for Help
The Landau Lab’s approach to a therapeutic vaccine centers on dendritic cells—a frontline player in the battle against infection, and the “brains” of the immune system. These cells patrol the body and, when they encounter a marauding virus or bacterium, ingest the invader, chop it up, and then display these fragments like flyers that allow other immune cells to recognize the infection. “Dendritic cells educate T cells,” explains Dr. Landau, “saying, in effect, ‘This is what HIV looks like. Your job is to kill any cells infected with HIV.’”
The insidious trick of HIV is to compromise the ability of helper T cells to call the killer T cells to action. It’s like disabling the body’s 911. To get around this impairment, Dr. Landau is targeting the dendritic cells, artificially arming them with fragments of HIV to present to killer T cells and equipping them with some of the stimulatory chemicals that would normally be provided by helper T cells. Vaccination with such engineered dendritic cells should allow those infected with HIV to activate their killer T cells and produce a targeted immune response. “The idea is to reinforce the immune system so that it can control replication of the virus,” says Dr. Landau.
Preliminary attempts by other labs to produce dendritic-based therapeutic vaccines have met with some success. “Two published clinical trials did show a short-term immune response,” notes Dr. Landau. “But then the virus rebounded.” That may be because these studies mixed synthetic preparations of viral fragments with dendritic cells before injecting these cells into patients. In such a preparation, the dendritic cells may present antigen fragments for a short time, but ultimately, the antigens get lost.
In the approach adopted by the Landau Lab, the dendritic cells are engineered with a gene that encodes a segment of HIV protein. These engineered dendritic cells are thus armed with a blueprint that allows them to continually produce the viral antigen they need to alert killer T cells to be on the lookout for HIV.
So far, the approach has worked well in a test tube. There, the engineered dendritic cells were able to stimulate human killer T cells and instruct them to recognize HIV, doing an end run around hobbled helper T cells. What’s more, the vaccine was able to coax dormant HIV hidden inside helper T cells to reveal itself. That observation was particularly promising, says Dr. Landau, because “if you can wake up latently infected cells and allow them to be recognized by T cells, the immune system can clear them.” Eliminating these latent HIV-infected cells depletes the viral reservoir, lessening the likelihood that one of these stowaway viruses can reawaken later, when the immune system may be unprepared, and ignite an explosion of replication that could lead to AIDS.
“Their approach takes advantage of how the body naturally detects retroviruses like HIV,” says Dr. Littman, a Howard Hughes Medical Institute investigator. You need to have this hardwired, innate mechanism, he explains, to mount a strong adaptive response, which includes the activation of both helper and killer T cells, as well as the production of antibodies that recognize the virus. “That’s the part that a lot of people working on HIV had ignored for the first couple of decades of research in the field,” he adds, “but it’s absolutely essential. This project bridges that gap.”
Not Just for HIV
Dr. Landau recently began collaborating with a team at the University of California, Los Angeles, to hone their vaccine in mice. In preliminary tests, he and his collaborators found that their dendritic cells restrained viral replication. “But the suppression lasted only about two months before the virus came back,” says Dr. Landau. “We think the T cells were getting exhausted”—activating the natural “checkpoint” mechanisms they use to shut themselves down once an infection has been eliminated, thereby preventing a runaway immune reaction. “But if you have a chronic infection, you don’t want those T cells to get turned off,” he explains. “You want to keep them active.” Now, the researchers are arming their dendritic cells with proteins that inhibit those checkpoints to keep killer T cells on their toes—the same strategy that’s used in a number of cancer immunotherapies.
While the current focus of this collaborative research is HIV, its promise extends beyond this one disease. “The cool thing about the research is that it has a number of potential applications,” notes Jeffrey N. Weiser, MD, the Jan T. Vilcek Professor of Molecular Pathogenesis and chair of the Department of Microbiology, who is involved in the launch of NYU Langone’s new Vaccine Center. “You can reprogram dendritic cells for a lot of different immune responses—to other infectious diseases and even to cancer.”
Indeed, Dr. Landau has found that reprogrammed dendritic cells can protect mice injected with melanoma cells from developing cancer. “We hope this is going to be a nice addition to the story,” he says. “It’s definitely going to be a big focus in our lab. At the end of the day, if you really want to make a breakthrough in HIV/AIDS, or any disease, you need bold new ideas.”