The quest for a cure
by Liz Highleyman
Thirty years after the first report of what would come to be known as AIDS, more and more researchers and advocates are talking about a cure for HIV – a development that is both shocking and long overdue.
"Hope for a cure is based on amazing progress in drug development and in understanding the underlying biology of HIV infection," said Paul Volberding, one of the first doctors to treat HIV and cofounder of the AIDS clinic at San Francisco General Hospital.
When the syndrome of opportunistic infections, wasting, and plummeting T-cell counts was linked to a virus, many believed it would not be long before effective treatment, a vaccine, and ultimately a cure would become available.
But HIV – which attacks the CD4 T-cells that coordinate the immune response –proved a wily foe. The advent of combination antiretroviral therapy (ART) in the mid-1990s dramatically reduced morbidity and mortality, and improvements over the past decade have enabled most people with access to treatment to reach an undetectable viral load.
Yet current antiretroviral drugs cannot completely eliminate the virus; HIV can silently hide in reservoirs such as long-lived memory T-cells and comes roaring back soon after treatment is interrupted.
Several changes during the past few years have made discussion of a cure no longer taboo, including greater understanding of how HIV evades the immune system and persists in the body.
"We've learned so much about the basic biology of HIV that we're willing to say aloud what has always been a distant dream: that HIV may be cured, not just controlled," Volberding told the Bay Area Reporter.
While ART can keep most HIV-positive people alive and relatively healthy, persistent immune activation and inflammation due to long-term infection can contribute to cardiovascular disease and accelerated aging, even in people with suppressed viral load and good T-cell counts. On the global level, there is a growing consensus that we cannot treat our way out of the epidemic.
From Berlin to California
Many people attribute renewed hope for a cure to the Berlin Patient, a man who appears to have eradicated HIV after a bone marrow transplant, providing proof-of-concept that a functional cure is possible.
At the 2008 Conference on Retroviruses and Opportunistic Infections, German hematologist Gero Hütter presented the case of Timothy Brown, an HIV-positive American man living in Berlin who required a bone marrow stem cell transplant due to untreatable leukemia.
Hütter's team managed to find a donor who was both a genetic match and carried an uncommon mutation that makes cells resistant to HIV infection. CCR5 is one of two gateways, or coreceptors, that HIV uses to enter cells. People who carry two copies of a genetic variant known as CCR5-delta-32 do not express this receptor on their CD4 T-cells, so most types of HIV are unable to enter.
(Photo: Rick Gerharter)
After his own cells were killed off with chemotherapy and radiation to eliminate the leukemia, Brown received two transplants of hematopoietic or blood-forming stem cells from a donor with the double resistance mutation – a procedure that essentially replaces the recipient's immune system with that of the donor.
Three years later Brown, who recently moved to San Francisco, remains off antiretroviral therapy and shows no signs of HIV in his blood, lymph nodes, gut, or brain.
This remarkable case led researchers to ask whether gene therapy could alter immune cells in a way that mimics the natural mutation. Richmond-based biotechnology company Sangamo BioSciences developed a zinc finger technique to delete the CCR5 gene from cells, rendering them resistant to HIV.
At this year's retrovirus conference in February, Dr. Jay Lalezari from Quest Clinical Research in San Francisco reported findings from a clinical trial of this approach in six participants with long-term HIV infection who had undetectable viral load on ART but still had low CD4 cell counts.
Participants had whole blood withdrawn and CD4 T-cells were filtered out. The harvested cells were sent to a laboratory to undergo the zinc finger procedure to remove CCR5, and the altered cells were then reinfused back into the patients. Five of the six participants experienced significant and sustained CD4 count increases, averaging about 200 cells.
"I was one of those people that over the years was finally able to reach undetectable [viral load] but my T-cells never recovered fully," said study participant and longtime AIDS activist Matt Sharp. "My hope in this trial was really to get my T-cells to a safe and normal range, which they appear to have done out to eight months."
Based on an ongoing analysis, Lalezari told the B.A.R. , "We remain enthused and we're encouraged that the study is moving in the right direction, but it's still too soon to know if this approach is going to provide true benefit."
Lalezari's team is currently recruiting additional participants for related gene therapy studies, including people who have not yet started ART, people experiencing treatment failure, and people with CD4 counts below 200.
While the CD4 cell approach could allow people to stay off ART for prolonged periods, using gene therapy to alter hematopoietic stem cells that give rise to all types of immune cells that may harbor HIV could potentially offer a permanent functional cure.
This strategy is riskier, but it has been shown to work in mice. John Zaia's group at City of Hope is now testing the approach in HIV-positive people who need stem cell transplants for leukemia, with funding from the 2004 stem cell ballot initiative that established the California Institute of Regenerative Medicine.
"Since my case had a huge impact on getting the thought of a cure back on the agenda, I am hoping that people will not see this as a done deal," Brown, the Berlin patient, told the B.A.R. "I am hoping for lots of effort and money to be directed toward a cure that may be attainable for everyone."
Scientists from government, academia, and the pharmaceutical industry are exploring a variety of other approaches to curing HIV.
Broadly defined, these fall into three areas, explained Dr. Steven Deeks from the Positive Health Program at SFGH: preventing any remaining low-level viral replication, enhancing the capacity of the immune system to seek out and kill HIV, and interventions that "can either reverse signals that force the virus into hiding or stimulate the virus so that comes out of hiding."
Researchers are currently testing a wide array of compounds to purge latent HIV from resting memory T-cells and other reservoirs. Once these silent viral genes are turned on and start producing new virus, they become visible to the immune system and can be targeted by existing antiviral drugs.
"We will undoubtedly learn a great deal with this first generation of ideas and hope to make breakthroughs, but it is certainly conceivable that our first ideas might not work," said Gilead Sciences researcher Romas Geleziunas. "However, since science is often an iterative process, this first generation might produce novel insights which will lead us to better ideas."
Advocates are devoting increased effort to promoting awareness of how far HIV cure research has come and encouraging more funding to enable it to go further.
"It's fantastic that we have 10 to 20 great scientists working on this, but we need a few hundred," said Stephen LeBlanc of the AIDS Policy Project. "Community pressure is critical for getting this research moving more quickly. Whether a cure becomes available in three years or 20 years makes a tremendous difference to the world in terms of the number of people who will be felled by HIV."
Indeed, most experts are hesitant to predict when a cure for HIV might be available, especially after decades of wrong guesses about HIV vaccines.
"Over the next five years we're going to see development of a variety of interventions that have a partial effect, and once we identify these various partially effective approaches, the next step will be to combine them to create a cure," Deeks told the B.A.R . "The first part is easier, the second part will be harder."
"Whether a cure is going to come from one approach or some combination, I do think its possible that in our lifetime we'll be curing HIV," Lalezari conjectured.
In the meantime, UCSF Positive Health Program Medical Director Bradley Hare encourages people with HIV to take advantage of state-of-the-art therapy available today.
"My belief is that when we have strategies that can lead to a cure, the people who are going to be in the best position to benefit will be those who have controlled HIV," he said. "Getting on treatment early, staying on treatment, and keeping the virus undetectable make those people most likely to be successful."
People interested in learning more about the Quest gene therapy trials can contact (415) 353-0800 or firstname.lastname@example.org.