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A Cure for HIV: Cracking the Code

March 30, 2016

Crack-the-codeIt is rare in the field of biomedical research that a complex scientific challenge can be reduced to a quartet of deceptively simple sounding steps. After thirty years of incremental progress and steady accumulation of knowledge — and close to half a billion dollars expended by amfAR, The Foundation for AIDS Research alone — we've reached such a juncture in our quest to find a cure for one of the most deadly viruses of our time — HIV.

The principal barrier to a cure is the reservoirs of persistent virus that remain in a person even after they have reached a so-called "undetectable" level of HIV as a result of antiretroviral therapy (ART). The four key questions that need to be answered all relate to these reservoirs: Where exactly in the body and in which types of cells are they located? How do they become established and how do they maintain themselves? How much virus do they contain? And, finally, how can we safely get rid of them?

HIV cure research has largely evolved from a process of discovery to a technological challenge. We need to develop the tools and agents to answer these key questions. Once we have answers, we can begin to cure some of the people some of the time, then most of the people most of the time. Ultimately, we hope, we'll have a safe and effective cure that can be made available to all who need it.

At the outset of World War II, the United States and its allies found themselves in a race against time and a Nazi war machine that was making alarming progress toward the development of an atomic bomb. And so the Manhattan Project was born. President Roosevelt marshaled the best scientific minds in the nation and provided them with the resources necessary to mount a massive collaborative effort and be first to the finish line.

However deadly its outcome, the Manhattan Project showed that getting teams of top scientists to collaborate in a focused, cohesive enterprise can lead to extraordinary results. Borrowing from that model, amfAR has established the amfAR Institute for HIV Cure Research. Founded as a collaboration among the University of California, San Francisco, the Gladstone Institute of Virology and Immunology, and the Blood Systems Research Institute, the amfAR Institute will also facilitate collaborations with research teams at Oregon Health and Science University; the University of California, Berkeley; Gilead Sciences; and the Infectious Disease Research Institute in Seattle, Washington.

The irony, of course, is that while the Manhattan Project was an all-out effort to build the most destructive weapon ever conceived by humankind, our task ultimately is to bring healing to the 37 million people living with HIV/AIDS worldwide and to end one of the deadliest infectious disease epidemics in history.

We, too, are on the clock. With more than 3,000 AIDS-related deaths and more than 5,000 new HIV infections every single day, the need for a cure is urgent. Even with the relative success of massive international HIV/AIDS programs like the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria, less than half of all people living with HIV are receiving lifesaving treatment. Even with recent advances in treatment, such as a once-a-day pill containing three different antiretrovirals, treatment remains a lifetime proposition and places a seemingly endless — and unsustainable — burden on many of the world's most fragile healthcare systems.

Given this urgency, amfAR has launched a $100 million Countdown to a Cure for AIDS initiative with the goal of developing the scientific basis of a cure by the end of 2020.

The institute is the cornerstone of this endeavor, and its researchers will focus on a strategy being pursued to effect a cure called "shock and kill" or "kick and kill." The idea is to find a way to awaken the virus in the reservoir, dislodging it from its hiding places in the body so that the infected cells producing the virus can be killed by the immune system or other interventions.

To achieve this, researchers must overcome some formidable scientific and technological challenges. Seeking out persistently infected cells is like looking for a needle in a haystack; they may account for only about one in a million infected cells. On top of that, until now there was no way to identify them. Researchers at the amfAR Institute and elsewhere are deploying cutting-edge tools such as microfluidics, positron emission tomography, and digital droplet technology to detect and quantify minuscule amounts of virus.

Institute researchers will initially focus their efforts on so-called toll-like receptors (TLRs), a class of proteins that play a key role in the innate immune system. Among other things, they will test several drugs called TLR agonists that can act on the receptors for their ability to reactivate virus. And they will test the effectiveness of a range of interventions in human clinical trials.

Timothy Brown — "the Berlin patient" — remains the only person known to have been cured of HIV. His cure was achieved as the result of a complex and high-risk series of procedures centered on a stem cell transplant, which he needed to treat his leukemia. Brown's physician was able to locate a stem cell donor with a rare genetic immunity that conferred resistance to HIV infection. The case was first reported in 2008, and Brown appears to be completely free of HIV to this day.

To date, no one has been able to replicate this cure, but a European consortium of researchers supported by amfAR aims to do so and is following several patients who have received similar stem cell transplants. The researchers are applying the kinds of tools mentioned above to pinpoint the locations of viral reservoirs in these patients and assess their size, while attempting to eradicate them altogether.

Is complete eradication necessary to effect a cure? Perhaps not. Some scientists believe this would be extremely difficult to achieve in practice and suggest a more likely cure scenario would involve the persistence of low levels of virus kept in check by a boosted immune system — more akin to the long-term remission typically associated with cancer patients. Clues to the feasibility of such a strategy may be derived from the so-called VISCONTI cohort, a group of patients in France who have been followed by researchers for several years. These patients began receiving ART within the first few weeks after they became infected, then for various reasons stopped taking their medication. Today they still have detectable HIV in their blood but have been off ART for an average of close to ten years without any signs of disease progression.

Several other promising avenues of HIV cure research, including therapeutic vaccines and boosted T cells, also are being pursued, while a number of researchers are looking at highly potent antibodies that can direct the killing of virus-infected cells. amfAR currently is supporting a clinical trial being undertaken by researchers in the U.S. and Europe who are testing whether a combination of a latency reversing agent that has shown promise and one of these potent antibodies can eliminate infection in people with HIV, or at least reduce the number of cells harboring the virus.

What will it take to cure HIV? Resources, to be sure. Unwavering commitment. Political will. More importantly, perhaps, this has to be a collective and international effort involving academia, government, industry, organizations such as amfAR, and foundation, corporate, and individual donor support. And here we can draw inspiration from a true hero of World War II whose genius and leadership saved countless lives by hastening the end of the war. "The search for new techniques," said British mathematician Alan Turing, who led a legendary team of cryptographers in cracking the Nazis' supposedly indecipherable Enigma machine, "must be regarded as carried out by the human community as a whole, rather than by individuals."

Headshot_kevin_frostAnd so it is with AIDS, an epidemic that has plagued "the human community as a whole" for thirty-five years and will require the collective efforts of that same human community to bring it to an end.

Kevin Robert Frost is chief executive officer at amfAR, The Foundation for AIDS Research.

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