By Matt Windsor

Standing by one graveside, then another, and still more and more, Alan Woellhart buried a generation of friends in the first few years of the HIV epidemic in the United States. His friends kept dying; eventually, he quit going. “Back in the early days, I stopped going to funerals when I lost my 50th friend,” Woellhart says.

HIV, the virus that causes AIDS, is very good at “working its evil,” as one UAB clinician puts it. The virus succeeds by hijacking helper T cells, which coordinate the body’s immune response against viral infections. Then it converts those cells into factories whose sole purpose is to pump out more HIV. Because the T cells die in the process, HIV has devised a way to maintain a steady supply of fresh victims. The virus induces captured cells to send out a call for backup before they die. When the reinforcements arrive, they become infected as well.

cover6Alan Woellhart has been living with HIV since 1989 and has taken part in the early trials of several key medicines. He saw dozens of friends buried before vowing not to go to another funeral. Eventually, over the course of 10 to 15 years, there aren’t enough helper T cells left to mount an effective immune response against the various bacteria, fungi, and other pathogens that always lurk on our skin, waiting for a chance to invade. It is these “opportunistic infections” that usually kill a person with end-stage AIDS. Once scientists understood this, an effort that took years, they could begin to find a way to fight back against HIV.

After Woellhart was diagnosed with AIDS on June 7, 1989, he came close to going under himself. He was saved by the arrival of AZT, the first drug approved by the U.S. Food and Drug Administration for the treatment of HIV. AZT targets an enzyme called reverse transcriptase, which HIV uses to make the copies of itself that it inserts into T cells. Finally, physicians had something to offer patients dying of AIDS.

“My first dose was delivered from a company in California, and when the UPS truck came, I ran out with a smile on my face, saying, ‘Now I’m going to be on something that will take care of me,’” Woellhart recalls.

AZT kept Woellhart alive, but the side effects were so devastating that he fled from it as soon as he could. “I joined a lot of research studies at UAB where I was one of the first people to ever take the medication,” he says. “I would be in the hospital for weeks at a time so they could monitor me. But I did it because if I was going to perish from the disease, I wanted them to learn something from me first.”

Progress and Promise

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UAB infectious diseases expert Michael Saag, M.D., was just finishing medical school in 1981 when the first AIDS diagnosis was reported. He made several seminal discoveries in the field, and in 1988 he founded the groundbreaking 1917 Clinic at UAB, which offers comprehensive care for patients with HIV and AIDS. That same year, UAB founded its Center for AIDS Research (CFAR), one of seven initial centers established by the federal government to advance research into the disease. Saag is now director of the UAB CFAR and holds the Jim Straley Endowed Chair in HIV Research.

Even as UAB researchers made dramatic progress in understanding the disease, however, they saw a parade of promising treatments end in failure. “I felt like every time a patient died, a part of me died with them,” Saag says. “I went to a lot of funerals, and after a time it became overwhelming to watch so many young people die.” Many died alone. One time a young woman found out she was HIV-positive when she came to UAB Hospital to deliver her baby. When the child died and the family found out the cause, they disappeared. No one came to the funeral except the mother, a social worker, and Saag.

The years passed, and despite the arrival of AZT, the funerals continued. When James Raper, D.S.N., C.R.N.P., joined the 1917 Clinic in the mid 1990s (he is now the medical director), “we had a death a week,” he says. Then came the breakthrough that everyone was waiting for—a new class of drugs called protease inhibitors. Woellhart had helped test early versions of the drugs when UAB researchers helped prove their efficacy to the FDA in the early 1990s. When protease inhibitors finally reached widespread use, says Raper, “the funerals slowed dramatically.”

Turning the Tide

Protease inhibitors work by blocking HIV’s ability to reproduce itself. But one antiretroviral drug alone can’t do the job indefinitely; eventually, HIV adapts and goes on killing. Researchers discovered that a combination of three different medicines could keep the virus at bay indefinitely, and highly active antiretroviral therapy (HAART) was born.

cover1Today people diagnosed with an HIV infection can live a normal lifespan, or close to it, says infectious disease researcher Michael Saag.“You can really divide the HIV epidemic into two distinct eras,” says Saag. “You have the first 15 years up to the mid 1990s, when HAART was introduced, and then the 15 years since, when we’ve been adding more effective, more tolerable versions of these drugs.

“If you are diagnosed with an HIV infection in 2012, before it’s too late—that is, before you get end-stage AIDS—and we get you on treatment, and you take your medicine, the virus will become undetectable,” Saag says. “You will live a normal lifespan, or something close to it. To get to that point within 30 years of the first report of AIDS is a tremendous success.”

UAB researchers played a major role in that success. They demonstrated the clinical value of measuring viral load (the amount of HIV in a sample of a patient’s blood), which is now the standard practice in HIV treatment. They were pioneers in testing the three-drug HAART “AIDS cocktail” combination that turned the tide against the disease. And UAB scientists were the first to trace the exact route of HIV’s spread from chimpanzees to humans.

How to:
Design a Successful HIV Vaccine

Vaccines work by exposing the immune system to a weakened example of an invading organism. That way it can be prepared for an overwhelming response when the real thing arrives. The problem with HIV is that it comes in more than 10,000 different forms; the likelihood that a person would get the exact form of HIV that matches his or her vaccination is negligible. But what if scientists could find a common link between the thousands of different HIV types? Researchers think they have achieved it, says UAB’s Paul Goepfert. His Alabama Vaccine Research Clinic is now taking part in an international trial that is putting the potential therapy through its biggest test.

“The objectives of research in HIV have changed dramatically during the last decade,” Saag says. “Before now, our focus was on developing drugs that would get the virus under control. We’ve done that. During the next five to 10 years, we need to find new ways to get people into care, we need to develop vaccines, and we also would love to have a cure.” Saag is confident that UAB scientists will provide vital clues to each of these puzzles. All three are major components of the new strategic plan adopted by the UAB School of Medicine and UAB Health System in 2011, he says.

Shot in the Arm

In the 1980s, as AIDS research shifted into high gear, scientists confidently predicted they would soon have a vaccine against HIV. Three decades later, they are still working on the problem, although the past few years have finally yielded some success, notes Paul Goepfert, M.D., director of UAB’s Alabama Vaccine Research Clinic.

“We’ve tested a large number of different vaccines over the years, but only three have actually gone on to be studied for efficacy,” Goepfert says. “One failed to show any protection and another seemed to increase the risk of HIV infection, but the third, which we’re working on now, actually showed success.”

That success initially came in a 2009 trial in Thailand. The vaccine, known as RV144, protected 60 percent of study participants from HIV infection after one year, although the protection rate fell to 30 percent after that.

cover3Paul Goepfert, director of UAB’s Alabama Vaccine Research Clinic, is taking part in an international trial of the first promising HIV vaccine in decades. UAB is one of 18 sites worldwide taking part in a trial of a new vaccine, HVTN 505, which aims to improve on the approach used in the RV144 trial. The trial is enrolling individuals who are HIV-negative but at high risk for contracting HIV; enrollment will continue through summer 2012.

Several features of HIV have complicated the search for a vaccine, Goepfert explains. One major problem is that there are thousands of different types of HIV, “and they can all cause AIDS,” he says. “We have wiped smallpox off the face of the earth with vaccines, and a big reason is that when you’ve seen one smallpox virus, you’ve seen them all. You can vaccinate with one type of smallpox, but if you only use one type of HIV, you’re going to induce antibodies for that one individual strain only, and there’s no way that’s going to provide protection against the large number of other strains of HIV.”

Another issue is the virulence of HIV. “For smallpox we used a live, attenuated [weakened] virus that induces all arms of the immune system very well,” Goepfert says. “We know from animal models that using live, attenuated viruses produces the best vaccines, but no matter how attenuated we make it, an HIV vaccine using a live virus still causes AIDS.”

Researchers once thought that they might have to target all 10,000 strains of HIV, but the RV144 vaccine tested in the Thai trial may have helped identify key targets that are shared by most HIV variants. “If you make a house with red bricks and a house with white bricks, they look different even though they follow the same plan,” Goepfert says. “We may have luckily stumbled upon a vaccine that recognizes the underlying structure of HIV.”

How to:
Cure HIV

Antiretroviral medicines are designed to interfere with HIV replication and block virus production. But a viral reservoir remains hidden in long-lived T memory cells, and as soon as a patient stops taking medicine, HIV is ready to launch a counterattack. Designing a cure depends on finding a way to flush out the dormant viruses so they can be targeted for destruction. UAB’s Olaf Kutsch is studying a class of medicines that may be able to do just that.

A successful HIV vaccine would significantly diminish the number of new cases and could put an end to the HIV epidemic, Goepfert says. But “it’s going to be much more difficult to create therapeutic vaccines that can be given to people who already have HIV,” he cautions. However, vaccines could be used to help control HIV for a time and allow patients to take a break from their medicine regimens, a so-called “drug holiday.” UAB researcher Sonya Heath, M.D., is currently studying the benefits of time-limited vaccine treatment.

“For the first time in a long time, we are closer to an HIV vaccine,” Goepfert says. “That’s great news.” The same could be true for that other holy grail of AIDS research: a cure. But long experience has taught UAB researchers to be cautious.

For the Cure

Modern antiretroviral drugs are so good at suppressing HIV replication that the virus often becomes undetectable in patients’ blood. But that is not to be confused with a cure, notes Olaf Kutsch, Ph.D., an associate professor in the Division of Infectious Diseases and member of the Center for AIDS Research.

“If a patient stops taking his or her medicine, the virus comes back in about three weeks,” Kutsch notes. To cure a patient with the current drugs, “you would need 40 to 60 years of therapy” to ensure that all infected cells were dead.

Most cells in the body live for only a few months, but HIV targets CD4-positive (CD4+) T cells, a vital part of the immune arsenal. CD4+ T cells “are like the captains on a ship,” Kutsch says. “They are very important in immune functioning. That is why HIV is so devastating.”

cover2Olaf Kutsch is looking for ways to force latent HIV out of its hidden reservoirs throughout the body—a crucial step in finding a cure for AIDS. Some of these infected CD4+ T cells, in turn, can become memory T cells, the Methuselahs of the body, which retain the immune system’s record of intruders it has faced in the past. Once HIV has become safely ensconced in a memory T cell, it can remain in hiding for years.

After HIV successfully integrates itself in a CD4+-cell genome, “it can’t be targeted by any of our drugs; it can just sit there as long as the cell lives, which could be a lifetime,” Kutsch says. In order to produce a curative therapy, “you need to use one of two strategies: reactivate the viruses from CD4+ cells or ‘freeze’ them so they can never become activated. And the first option is the one everybody works on because it seems more feasible.”

In the laboratory, researchers already know several ways to stimulate memory cells, which triggers virus reactivation. The trouble is, it also stimulates a massive immune response, producing a wave of signaling molecules known as cytokines. This “cytokine storm” is similar to anaphylactic shock, and it can be fatal. “So the prerequisite for any curative therapy against HIV is to dissociate HIV reactivation from cytokine production,” Kutsch says. His lab has been searching for an agent that would do just that, and it recently found some interesting candidates.

“We have discovered that there are a number of FDA-approved cancer drugs that can be used to prime latent HIV for reactivation,” Kutsch says. Laboratory experiments have shown some promise, but a lot of development would still have to be done before this approach could ever be tested in the clinic, Kutsch notes.

Falling Through the Cracks:
The HIV Treatment Cascade

Of the 1.1 million Americans estimated to be living with HIV, 21 percent remain undiagnosed; 31 percent are either not linked to care or their care has been delayed, worsening the infection; and 41 percent have not been retained in care after they began treatment. This means that out of that 1.1 million, only 19 percent have a suppressed viral load, the marker of a successfully contained infection.

Because the drugs are already FDA-approved for another condition, the typical 15-year timeframe from basic-science discovery to final product could be compressed. But it will still be years, if ever, before the discovery results in a patient-ready therapy, he notes. “Unfortunately, there is nothing fast in this line of work,” Kutsch says.

Raper, who says he gets an avalanche of inquiries every time an AIDS research breakthrough hits the news, still hasn’t lost hope that science will find a way to end the scourge. “I am always looking forward to the day there’s a cure,” he says. “I don’t know if it will happen in my lifetime, but we are certainly making great advances.”

The Long Tail of an Epidemic

Despite the success of HIV drugs—in fact, because of that success—the AIDS epidemic continues to rage in the United States, even though it is largely forgotten by the wider culture, says Michael Mugavero, M.D., associate professor in the UAB Division of Infectious Diseases and director of the clinical core of UAB’s CFAR.

“There are now 1.1 million Americans living with HIV/AIDS, and there are 56,000 new HIV infections reported annually—a number that has remained stable for more than a decade,” says Mugavero. Because of lifesaving antiretroviral drugs, the annual death toll from AIDS has dropped to around 18,000, which means that the number of survivors grows by tens of thousands each year. And as it does, many Americans slip through the cracks.

Several innovative ideas pioneered at the 1917 Clinic are attracting national attention, Mugavero notes. UAB’s Project CONNECT helps new patients develop relationships with the entire medical team at the clinic and speeds the beginning of treatment. The clinic’s Orientation Team meets with all new patients within five days to collect a complete medical, emotional, and contextual history; explain all the resources available at the clinic; obtain the initial lab work necessary for the doctors to make treatment decisions; and schedule the first doctor’s appointment. The goal is to have everything in hand by that first appointment so that the entire care team has a game plan in mind, Mugavero says.

Another idea adopted at UAB draws on a successful approach to cancer care. “Patient navigators” help patients make appointments, enroll in government and private programs to help pay for medicines and transportation, and even find housing and food assistance through available clinic and community resources.

“We have built up a great model here over the years,” Mugavero says. “You start out by describing and identifying problems and the patients at highest risk. Then you have the information you need to give you ideas about what you can do about it.”

It has been a challenge to spread the great ideas developed at specialty centers like UAB to the wider HIV care community, Mugavero notes. In March, however, an expert panel for the International Association of Physicians in AIDS Care, which included Mugavero, released the first comprehensive guidelines offering research-based recommendations on how HIV service providers can get more patients into care, and retain them in care. “This has been a long time coming,” Mugavero says.

Prevention As Cure

One of the most exciting developments in HIV research is the discovery that antiretroviral drugs benefit more than the people who take them. It all goes back to a 2000 study in the New England Journal of Medicine showing that individuals whose viral load was below a certain threshold did not transmit the infection to their partners.

In August 2011, another study showed that the initiation of antiretroviral treatment brought a 96 percent reduction in transmission to uninfected sexual partners. “We have proven that you can prevent new infections by treating people with HIV,” says Michael Mugavero, M.D., associate professor in the UAB Division of Infectious Diseases and director of the clinical core of UAB’s Center for AIDS Research.

Efforts focused on protecting those who are HIV-negative also received a boost recently from a 2010 study based in South Africa, which found that the antiretroviral microbicide gel Tenofovir, applied to the vagina up to 12 hours before or after sex, reduced new infections by 39 percent among study subjects. UAB is now serving as one of three sites testing the safety of a vaginal ring that delivers two antiretroviral drugs and is inserted monthly. The trial will enroll 48 HIV-negative women ages 18 to 40, with results expected by early 2013.