Genetically engineered T cells render HIV's harpoon powerless

[kamrananvaar]

When HIV attacks a T cell, it attaches itself to the cell's surface and launches a "harpoon" to create an opening to enter and infect the cells. To stop the invasion, researchers from the Penn Center for AIDS Research at the University of Pennsylvania and scientists from Sangamo BioSciences, Inc. have developed genetically engineered T cells armed with a so-called "fusion inhibitor" to disrupt this critical step and prevent a wide range of HIV viruses from entering and infecting the T cells. The findings were reported today online in a preclinical study in PLOS Pathogens.

HIV medicine experienced a breakthrough in the early 2000s with a unique class of drugs known as "fusion inhibitors." Unlike most drugs that block virus replication inside of T cells, these drugs prevent HIV from entering cells in the first place. The drug, enfuvirtide, modeled after a peptide from the viral envelope and used today in combination with other antiretroviral therapies, has been shown to keep the virus at bay. However, patients need to inject enfuvirtide daily under their skin, limiting its utility and acceptability to patients, especially when compared to many other orally available drugs. HIV can also become resistant to enfuvirtide.

Building on this approach with a powerful genetic technique, researchers developed a novel way to deliver the fusion inhibitor peptide precisely to the spot on the cell surface where the virus attaches and launches its envelope, like a harpoon. The team genetically altered T cells by introducing a so-called C34 peptide, modeled after enfuvirtide, directly onto receptors, CXCR4 and CCR5, which are crucial for HIV entry. By using these molecules to deliver the C34 peptide to the site where the virus enters, these investigators showed that HIV was potently inhibited and that this inhibition extended to genetically diverse HIVs, including those that were resistant to the drug, enfuvirtide.

The most impressive results were seen when the C34 peptide was attached to CXCR4, where the Penn investigators showed that T cells expressing this molecule were protected in a mouse model of HIV infection.

"We believe that our approach to precisely target an inhibitory drug to the site of viral entry creates a new way to engineer human T cells to become resistant to HIV infection," said senior author James Hoxie, MD, a professor of Medicine in the division of Hematology/Oncology in the Perelman School of Medicine at the University of Pennsylvania. "It's potent and very broad. Every strain of HIV we tried was sensitive to it, regardless of whether the virus used CCR5 or CXCR4, which is a big advantage, since HIV typically uses CCR5 to establish infection, but can over time, evolve to use a CXCR4 instead. With this approach, it doesn't matter where the virus came from or what cellular molecule it needs to infect cells."

The findings set the stage for an upcoming phase I clinical trial in HIV-positive patients to determine the safety and appropriate dosage of a patient's own T cells engineered to express the C34-CXCR4 molecule, as well as to demonstrate their ability to resist infection when antiretroviral therapy is interrupted.

The research team also includes James L Riley, PhD, an associate professor of Microbiology, Pablo Tebas, MD, a professor of Medicine and director of the AIDS Clinical Trials Unit at the Penn CFAR, along with co-first authors, George Leslie, PhD, a senior research investigator in Hoxie's lab, Jianbin Wang, PhD and Michael C. Holmes, PhD, of Sangamo Biosciences, Inc. and Max W. Richardson, PhD, a senior research investigator in Riley's Lab.

Peptides derived from the HIV-envelope protein inhibit HIV entry by interfering with the formation of what is termed the 6-helix bundle during fusion of the viral and cellular membranes that occurs during viral entry. This is how enfuvirtide works, although when injected as a drug, enfuvirtide is distributed throughout the entire body. In the work described by the Penn and Sangamo researchers, performed in the laboratory and in a humanized mouse model, the C34 peptide attached to the CXCR4 molecule delivered the peptide to where fusion was actually occurring.

In the lab, the researchers found that T cells expressing either C34-CCR5 or C34-CXCR4 were enriched in the presence of HIV infection, going from 25 percent of the T cell population to greater than 60 percent after 7-10 days of additional culture. This enrichment was observed against a wide array of HIV strains, suggesting that this approach will be highly effective in a vast majority of individuals. Similar data was obtained using a humanized mouse model of HIV infection. In the experiments, only CD4 T cells expressing C34-CXCR4 were able to resist HIV infection and survive within the mouse. For this reason, C34-CXCR4 was chosen to be used in a phase I clinical trial.

This work builds off past experimental, genetic HIV techniques. In 2014, Penn researchers successfully genetically engineered the immune cells of HIV positive patients to resist infection, and decreased the viral loads of some patients taken off therapy entirely. The group used the zinc finger nuclease (ZFN) technology developed by Sangamo BioSciences to modify the T cells in the patients—a "molecular scissors," of sorts, to eliminate the CCR5 surface proteins. Without it, the virus couldn't enter. However, there are some limitations with this approach: it only addresses viruses that use CCR5 and both CCR5 alleles need to be knocked out for the T cells to be protected from infection.

The clinical trial investigating the work with C34 is slated to start in December 2016. The researchers will infuse C34-CXCR4 expressing T cells into well-controlled HIV infected individuals. It will be a dose-escalation study in which 1, 3, or 10 billion engineered T cells will be infused. After infusion, an "analytical treatment interruption" will occur for about 16 weeks and time to viral rebound and enrichment for the C34-CXCR4 expressing cells will be monitored. At present, patients infected with HIV must continue to take anti-HIV drugs to prevent the virus from replicating and causing disease. Efforts are underway at Penn and throughout the world to develop strategies that will enable drug therapy for HIV to be discontinued safely.

"This may provide a successful novel strategy to supplement anti-viral immune responses that complement approaches to target or control HIV reservoirs in patients infected with the virus," the authors said.

Explore further: New lead against HIV could finally hobble the virus's edge

Journal reference: PLoS Pathogens

Provided by: Perelman School of Medicine at the University of Pennsylvania

 

[kamrananvaar]

Exciting Antibody Discovery Sparks New Hope For Future HIV Vaccine
Scientists have discovered an antibody that can powerfully neutralize many variants of the most common strain of HIV, opening up a door for researchers to explore treatment and prevention options for the potentially fatal virus.

Antibodies ― proteins created by our immune system that are in charge of spotting and neutralizing potentially harmful substances in our body ― are promising avenues for potential vaccines and treatments against the virus.

The new antibody, named N6, was isolated from the blood of a person with HIV. It managed to neutralize 98 percent of the HIV variants that researchers tested it on, including 16 out of 20 variants that are usually resistant to this kind of antibody protein.

A previous antibody discovered six years ago, VRC01, had only been able to neutralize about 90 percent of HIV variants. Until now, it was considered the “gold standard” in terms of what the human body could produce to fight the virus, explained Dr. Justin Bailey, assistant professor of medicine at Johns Hopkins University School of Medicine.

“As each of these new antibodies is isolated, we don’t know if that’s the best it’s going to get,” said Bailey, who wasn’t a part of the National Institutes of Health team that discovered N6. “This antibody proves that we haven’t reached the ceiling yet in terms of how broad and potent neutralizing antibodies against HIV can be, because we’re getting close to 100 percent coverage with N6.”

This antibody proves that we haven’t reached the ceiling yet in terms of how broad and potent neutralizing antibodies against HIV can be.Dr. Justin Bailey, Johns Hopkins University School of Medicine
While scientists have been trying for years to isolate these broadly neutralizing antibodies, or BNABs, in the blood of people with HIV, they’ve struggled to find an antibody that is strong enough to work on many different variants of the virus. This is because HIV is really good at evolving to evade antibodies by rapidly changing the proteins on its viral “envelope,” which prevents antibodies from recognizing the virus, attaching to it and killing it.

But the reason N6 is so exciting to researchers is that the antibody has a way to attach to the virus that doesn’t depend on recognizing the constantly changing surface proteins on the virus. Instead, it attaches to a part of the virus that doesn’t change much from variant to variant, which is why N6 appears to be so effective at neutralizing so many different versions of the virus. The N6 antibody has also found a way to avoid the carbohydrates on the HIV virus that block antibodies from binding to it.

“We have an antibody now that essentially compensates for most of the diversity of the virus,” said Bailey. “The next big step is trying to design a vaccine that could induce an antibody like this, because if you could induce an N6-like antibody at high enough levels in vaccinated people, they’d probably all be protected against most HIV infections.”


Experts are optimistic about the discovery of N6, but they also caution that researchers are still a long way from creating a safe, effective vaccine or treatment.

“I don’t want to give the sense that a vaccine is around the corner ― we’ve heard that predicted so many times,” said Dr. Paul Volberding, director of the AIDS Research Institute at the University of California, San Francisco. “We’ve seen so many developments, but [N6] is certainly of great interest and something that we will follow closely.”

Research on the VRC01 antibody illustrates Volberding’s caution perfectly. The VRC01, which is one of the first well-characterized antibodies to be isolated, is currently being tested in several clinical trials to see if it can prevent HIV infection via intravenous infusion. So far, researchers have found that the VRC01 antibody can delay the rebound of HIV if a person stops taking antiretroviral therapy, but only for eight weeks, at most.

Volberding hopes that if VRC01 is combined with other effective BNABs, it could be strong enough to work as a vaccine in the future. But as it stands, he said, VRC01 alone doesn’t appear to be potent enough to create a functional cure for people with HIV.

HIV expert Dr. Jeffrey Klausner of the UCLA David Geffen School of Medicine also said it was too soon to know what the N6 discovery means for the prevention or treatment of the disease. He said that creating an HIV vaccine is the only true way to control the epidemic, but it may be more than 10 years away.

This really gives cause for optimism that the immune system, when stimulated properly, really can overcome and match the diversity of the virus.Dr. Justin Bailey, Johns Hopkins University School of Medicine
Not everybody who gets HIV will produce BNABs that can mount a vigorous defense against different variants of the infection. Some researchers estimate that only 10 to 30 percent of people with HIV produce them, while others estimate that number to be only 1 percent. These estimates vary because of the different ways BNABs are categorized, and just how many variants of HIV they can actually neutralize.

People with long-term HIV infections typically produce these special antibodies after several years, which means it’s too late for a person’s body to eradicate the virus completely. However, they show that some people’s bodies continue to try to create antibodies to fight the infection.

“There has always been pessimism that the diversity of the virus has been so great that the immune system could not match it,” Bailey said. “This really gives cause for optimism that the immune system, when stimulated properly, really can overcome and match the diversity of the virus.”

Since it was first discovered, more than 70 million people worldwide have been infected with HIV and about 35 million people have died. Currently, about 1 percent of all adults in the world, or 37 million people, have the disease. Only 46 percent of them are being treated with antiretroviral therapy. Last year, 1.1 million people died of AIDS-related complications.

 

[kamrananvaar]

Did Scientists Just Discover How to Stop the Spread of HIV?
Unlike other failed approaches, this stops the virus from replicating
By Sage Lazzaro • 11/21/16 2:28pm
published their findings Friday in the journal Nature.

So far, the laboratory studies have been conducted on mice. In order to introduce a vaccine, the researchers administered a rhinovirus (or common cold virus) that had been altered to include HIV proteins into the noses of the mice. At the same time, the mice also received injections containing a DNA-based vaccine.

‘The findings of our work now support the need for further testing of this targeted approach to an HIV vaccine.’ – Eric Gowans

The results showed this method could provide a solid first line of defense against HIV in humans.

“A possible reason why previous HIV vaccine trials have not been successful is because of this lack of a frontline protection,” senior author Dr. Branka Grubor-Bauk, from the Discipline of Surgery at the University of Adelaide and Basil Hetzel Institute for Translational Health Research, told MedicalXpress.

“Importantly, this vaccine approach encompasses two different arms of the immune system: white blood cells that attack the HIV virus and specific antibodies that recognize and shut down HIV-positive cells,” he added.

Where most approaches have failed but this one succeeds is in the way the combined treatment prevents HIV from replicating itself. This happens so rapidly that until now that researchers have had difficulty finding a way to stop.

“Overall, we found that infection was considerably reduced in the mice we studied. The findings of our work now support the need for further testing of this targeted approach to an HIV vaccine,” Eric Gowans, head of the Virology Group conducting this research, said.

 

[Deidara]

One day people will lose jobs at the rubber factory

 

[kamrananvaar]

Louis Picker stomped through the house, growled at his dogs, then slumped down at the bottom of the staircase, dejected. “I can’t do it anymore,” the immunologist told his wife.

“Yes, you can,” she said.
“It’s not going to work,” he said.

“It’s going to work,” she replied. “It’s going to work.”

Picker has had this conversation with his wife, Belinda Beresford, several times, because after 30 years of immunology research, the 59-year-old is on the verge of launching human trials for a vaccine that could stop AIDS, an epidemic that has become something of an afterthought decades after it began ravaging gay men in America. For many in the developed world, complacency has set in, largely thanks to a regimen of antiretroviral drugs that allow people with HIV to live long and healthy lives, and decades of failed attempts to develop a vaccine. Much of Picker’s work now involves fighting for grant money in a dwindling pot of research funds to keep his laboratory at Oregon Health & Science University running. To win those grants, he must continually prove that his unorthodox approach to creating a vaccine is probably going to work, which means that he needs a string of victories in the laboratory. “Science has its ups and downs,” he says. “You only get rewarded for the ups.”

Each day’s progress is critical. Picker’s vaccine has shown remarkable results in rhesus macaque monkeys—results that HIV researchers closely watch. “There’s a pretty strong consensus that it’s one of the two or three most promising approaches we have in the field,” says Guido Silvestri, a leading immunologist at Emory University School of Medicine . “This is not just a monkey curiosity.”

But promising is not enough, and just one tough morning in the lab might mean the whole thing’s over. “Sometimes, he doubts himself,” Beresford says. “He’s tired. He has a rambunctious 6-year-old. He feels guilty because he’s not home enough.”

Fortunately, Picker is dogged, and Beresford is patient—the two married about eight years ago and have yet to go on a honeymoon. After he growled at their dogs that night, she poured him a shot of Laphroaig, his favorite scotch, and sat with him in a guest room that has five vintage steel Colnago bicycles hanging on the walls. Picker sipped his whiskey and gazed at his bikes, hoping he’ll someday have enough free time to ride them every morning. But he won’t have that luxury until he can prove his AIDS-orphaned stepson, Thabo, correct. “LP’s gonna do it,” the 17-year-old likes to say. “LP’s gonna stop AIDS.”

Louis Picker, M.D., of the Vaccine and Gene Therapy Institute at Oregon Health & Science University, Picker, is on the verge of launching human trials for a vaccine that could stop the AIDS virus.OHSU/BOONE SPEED

A Wily Enemy
Picker first met Thabo in Johannesburg in 2009, a few months after meeting Beresford, a journalist who had interviewed him for a story. She had adopted Thabo when he was 2. He was a stubborn, independent child with big brown eyes, born virus-free even though his biological mother had AIDS. Thabo considered strangers cautiously, so when Picker arrived at the airport to meet him, he brought two suitcases. One carried his clothing. The other contained baseball gloves and an American football to beguile the 9-year-old.

Now, seven years later, Picker lives in Portland, Oregon, with Beresford, Thabo and five other children, four from previous relationships and one they had together. Long before their family took shape, Picker was working to stop the spread of HIV. His fight began during his residency in Boston in the early 1980s, in the first years of what would become the global AIDS epidemic. “It was sort of a rumor then,” Picker says. “The storm was coming.”

In 1984, U.S. Secretary of Health and Human Services Margaret Heckler expressed hope that the storm would subside, that science might have a vaccine for HIV within two years. Instead, a decade passed, and by 1994, AIDS was the leading cause of death for Americans ages 25 to 44. In the past three decades, four vaccines have made it to human trials, but none made it to market.

Picker published his first paper on AIDS in 1985 but then shifted his focus away from the disease; he went to Stanford to study immunopathology and hematopathology. But as the years dragged on, people close to him—a cousin, a classmate, a friend—died of AIDS. “It had an impact on me,” he says. “It resonates with you in a way that somebody who’s 90 and dying of cancer doesn’t. It’s personal. It’s a titanic struggle against a very wily enemy.”

By 1993, the National Institutes of Health (NIH) had begun a hunt for immunologists interested in AIDS research. (The field had previously been dominated by virologists, who had a better understanding of the vector and the virus, than the immune system’s response.) The agency offered to throw grant money at the problem. “I immediately switched,” Picker says.



Two years later, he began working on a new approach to studying T cells, which keep us healthy by remembering how to fight pathogens (disease-causing microorganisms) that they’ve already come across. Each time they encounter a pathogen, T cells specific to it rush into battle, expanding and migrating via the blood into the tissues.

When pathogens stimulate T cells, they respond by deploying small molecules called cytokines to knock out the infection. Picker devised a way to understand these cytokines inside T cells, which “revolutionized the field of immunology,” says Andrew Sylwester, the manager of Picker’s lab, “even though he doesn’t get credit for it.” His “cytokine flow cytometry” allowed him and other scientists to not only count cytokines but know their function.

Picker needed a virus on which to test his technique. In those days, it was too difficult to acquire blood from HIV-positive subjects, and experts wrongly assumed those infected with the virus had poorly functioning immune systems. He considered mumps but soon found a better adversary: cytomegalovirus (CMV), a virus in the herpes family. This was ideal because half of the U.S. population is infected with it, most without symptoms.

His technique worked, and it helped researchers learn how CMV affected the immune system. Previous studies revealed that the body’s T cells responded to the virus, but until Picker came along, no one had been able to examine the quality and quantity of the cells’ response. In 2001, Picker replicated the results of the CMV assay using blood from HIV-positive subjects—while people with AIDS continued dying by the hundreds of thousands each year.

Herpes Can Help
As Picker continued his research, scientists developed a series of antiretroviral drugs that slowly downgraded HIV to a chronic disease, as opposed to a deadly contagion, at least in the developed world. But globally, AIDS is still killing a lot of people, largely because most of those infected in poorer countries don’t have access to the drugs. According to the World Health Organization, 1.1 million people died from AIDS in 2015. In the U.S., 50,000 new cases of HIV are reported every year. Worldwide, the number is 2 million. Every time news reports come out about Picker’s research, he fields a series of phone calls from HIV-infected patients, their friends and their family. “Can I be in your trial?” people ask him. “Please, can you save my son?”

Much of the HIV research today is focused on finding better antiretrovirals. Efforts to create a vaccine have centered on generating antibodies that find pathogens in the blood, smother an infection before it takes hold or manipulate T cells into fighting off the virus. The measles vaccine, for example, encourages T cells to fight in response to the inoculation, after which they go back to a resting state. “The soldiers go back to the base,” Picker says. When the pathogen returns, the T cells reactivate. “They grab rifles and arm themselves, but it takes two weeks.”


Against HIV, T cells are outgunned. The virus replicates quickly and is “immune-evasive,” meaning it can overwhelm or dodge the immune system’s attempts to fight, leaving T cells no time to mount an adequate defense before the virus has taken root. What’s worse, HIV embeds itself in T cells, which means the T cell response to an HIV onslaught leads to its own destruction—the proliferating T cells actually spread the virus.

Picker’s CMV research led him to wonder if he could trick the body’s T cells into creating and maintaining an “armed” response to a virus to which they’d never been exposed. That would allow the T cells to react quickly when first confronted with an HIV infection. CMV presented a new opportunity, because the virus leads to an extraordinary effort by T cells, which is why 80 percent of the population is carrying it without developing symptoms.

Top HIV researchers say this approach could be combined with a more traditional antibodies-based vaccine. Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, created one that’s headed for human trials. His method focuses on antibodies, which can have a difficult time spotting the swift-moving and mutating HIV. But combining his approach with Picker’s could be effective—the antibody method could prevent some infections, and Picker’s technique could knock down the ones that slip through. “Louis’s program is one of the most creative, innovative and impactful efforts in the field,” Barouch says. “The data is very promising.”

But so far, only for monkeys.

Blood and Monkeys
For more than 15 years, Picker has been working at the Oregon National Primate Research Center, home to more than 5,000 rhesus macaque monkeys, 21 baboons and, more important, Jay Nelson, one of the world’s foremost experts in CMV.

On a steel table deep inside the lab in Beaverton, Oregon, researchers sedate three female rhesus macaques so they will more willingly submit to a blood draw. Tattooed with numbers to identify each of them, they’ve all been inoculated with Picker’s CMV vaccine to see if it will allow them to fight off the simian immunodeficiency virus (SIV)—the monkey version of HIV. The vaccine works by adding HIV genes into a weakened form of CMV, which tricks the T cells into arming themselves to battle the virus.

In 2008, two years after Picker began vaccinating monkeys against SIV, four of the 12 macaques inoculated proved his vaccine could work: They’d knocked infection levels back to a minimum, and SIV didn’t take root. Four years later, the results improved. Of 150 inoculated animals, more than half were effectively cured. Picker’s findings were published first in the journal Science and then in Nature in 2013. “It’s a biologically stunning result,” says Marcel Curlin, an Oregon Health & Science University infectious disease specialist running the HIV trials. “For the first time, he trained the immune system to clear a virus from an infected animal. It sent huge shockwaves through the HIV community and fueled an enormous enthusiasm and energy to move the program forward.”

Picker’s vaccine has shown remarkable results in rhesus macaque monkeys, which AIDS researchers say is very promising.WINSTON ROSS FOR NEWSWEEK

The monkey results are some of the most promising news in HIV research since a clinical trial that took place in Thailand between 2003 and 2009. The trial combined two vaccines, and that cocktail reduced the rate of infection among participants by 31 percent. It was encouraging but not good enough to be a marketable vaccine.

Then came terrible news, in a different trial. From 2004 to 2007, 3,000 patients considered at high risk for developing HIV enrolled in a trial to test a vaccine developed by Merck. The idea was not to prevent infection but to control the viral loads after infection, so subjects could survive. It didn’t work. Not only did the vaccine fail to stop HIV, but there was a 48 percent higher rate of infection in the group that received the vaccine than among those who took a placebo. Researchers were dismayed. “Merck pulled out altogether,” says Curlin. “Many programs shut down. People changed careers.”

The lesson, says Silvestri: “It’s really hard to make a vaccine. The field was much more pessimistic after the Merck trials.”

Picker, however, was undeterred. “I predicted the outcome of the Merck trial. I knew it wouldn’t work. It’s a T cell vaccine, but it’s very different from our T cell vaccine. It didn’t discourage me at all.”

But he did ask Tony Fauci, director of the NIH, if the Merck trial would dampen support for similar work, if the research community would give up. Fauci’s response: “We’re not going to give up. We’re going to double down.”

Expensive, Slow and Frustrating
In the early development lab at the primate center, Wilma Perez, one of Picker’s research associates, spends her days infecting dozens of flasks of cell cultures with CMV, sometimes as many as 150 a day. She is careful to don protective clothing, booties, a mask and gloves before entering one of the lab’s highly sensitive areas. Any kind of contamination—mycoplasma, fungus, mold, bacteria—could shut down the process and delay the vaccine manufacturing. Because the virus takes weeks to grow, there isn’t time to spare.

Picker’s lab is racing to make enough of this vaccine by the time the trials are supposed to begin, because its funding could run out. Oregon Health & Science University is competing against more established institutions that have much more experience in the field. There’s also the danger that support will dry up as the virus increasingly becomes a problem of only developing nations. That means Picker’s research needs to show more results as quickly as possible, so neither he nor any of his 25-person staff knows what a “normal” workweek looks like.

The team’s results are promising, but they need to improve before they can bring a vaccine to market. “It only worked in 50 to 60 percent,” Picker says of the macaque results. “How do we make it 100 percent?”

Picker may be in a hurry, but he doesn’t rush the science. “If I had another 40 years, I’d be absolutely sure it would work. [But] I want to get this done in the next 10 or 12 years. All it takes is somebody at the NIH or high up in the Gates Foundation to say it’s done, it doesn’t work, and we’re dead.”

He’s on his way. In June, the NIH awarded Picker’s lab $14 million to continue his work (Barouch got the same amount), a nice addition to the $25 million grant he landed from the Bill & Melinda Gates Foundation in 2014. But human trials will cost 10 times that amount, Picker estimates, so his fundraising can’t stop. “It’s really expensive. It’s really slow. It’s really frustrating,” he says. “This is not like designing a new iPhone. This is something that’s been designed for millions of years, by nature, by iterative mistakes, and we’re trying to unravel it.”

If this vaccine works in humans—and Picker is optimistic it will—it could be combined with therapeutic drugs or other vaccines to effectively cure the virus. And, in theory, Picker’s CMV experiment could be useful against other illnesses too: tuberculosis, malaria, herpes simplex 2, hepatitis B and maybe even some forms of cancer, because all of those diseases attack T cells in a similar way. “Imagine you have a soldier with a gun,” Picker says. “The gun is the same, but now he has goggles that can see x, y or z enemy.”

For any of Picker’s soldiers to be deployed in the real world, though, he will have to make a vaccine that not only works but can be produced cheaply enough that pharmaceutical companies can make a profit. “The government doesn’t make vaccines,” he says. “Big Pharma makes vaccines. Big Pharma doesn’t want to pay for the research; they want to swoop in and take it over.”

Picker will be thrilled if that happens, because bringing a drug to market is the only way his vaccine can save lives. And then, maybe, he’ll get to go on his honeymoon.

 

[kamrananvaar]

New HIV vaccine trial, the first in years, to begin
human immunodeficiency virus, researchers were encouraged four years ago when a test of a vaccine on 16,000 people in Thailand turned up a previously unknown vulnerability in the resilient pathogen.

The vaccine was only 31 percent effective and wore off over time, so it could not be approved for use in a general population. But the study's results allowed scientists to exploit the chink in HIV's armor, reformulate the drug and bring it back for another clinical trial.

Now all eyes are on South Africa, where researchers will begin inoculating thousands of volunteers Monday in the latest - and, some say, most promising - effort to develop a vaccine that prevents the disease. It is only the seventh full-scale human trial for a virus that infects more than 2 million people and kills more than 1 million every year.

"If this study shows efficacy . . . this would be a tectonic, historic event for HIV," said Nelson L. Michael, director of the U.S. Military HIV Research Program, which led the Thailand study.

Tanzania suspends HIV/AIDS programs in new crackdown on gays
For 18-year-old S'phindile Dlamini, another volunteer who is no relation to Thembi, it was a neighbor whom she remembers dying first. In their community, people normally pitched in when someone fell ill. But the more brittle this woman grew, the farther away people stayed and the louder they whispered.

Between them, Thembi and S'phindile also count a niece, teacher and friends among their losses.

Though HIV has faded from the headlines since the development of antiretroviral drugs made the disease manageable, it is still a pandemic. About 36.7 million people worldwide were living with HIV in 2015, including about 2.1 million who were newly infected, according to the Joint United Nations Program on HIV and AIDS. In the United States, the Centers for Disease Control and Prevention says 1.2 million people are infected.

Globally, 18 million people were able to get the medicines they needed to control the virus last year, according to the U.N. HIV program.

South Africa has more than 7 million people living with the virus. In some parts of the country, such as the northeastern coastal province of KwaZulu-Natal, where Verulam is located, estimates place the number of HIV-positive people at nearly 30 percent.

There is no preventive drug and no cure. Yet this is the first new human HIV vaccine study in about a decade.

"We need to test more vaccines," said Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. "In over 35 years of the epidemic, we've only tested four different HIV vaccine concepts. We need more shots on goal."

But these trials, which have a long history of failure, are difficult to design. They are large, complicated and expensive. And the virus, because of its variability, is an extremely resilient target.

"All of those bugs for which humanity has made vaccines do not insert themselves into the genome of the human they are infecting," said Barton Haynes, director of the DukeHuman Vaccine Institute at Duke University. "HIV inserts its genetic material into the genetic material of the person it infects. That's why we can't cure it."

In 2007, South Africa was one site of a second phase of testing for an HIV vaccine developed by pharmaceutical giant Merck. The study was called off soon after it began, however, when early results from other locations showed that the vaccine seemed to be making people more susceptible to HIV than a placebo.

Results from the new study are not expected until 2020, though the test could be ended earlier if it shows spectacular results or unexpected problems.

"If we knew we were going to be successful, we wouldn't have to do the experiment, but we do believe this approach has great promise," said Glenda Gray, president of the South African Medical Research Council. The longtime HIV researcher is leading the trial. "We've grown used to being wrong because of all the failures we've had in the HIV field, and I think all of us are quite pragmatic, but we're still excited."

Some of that same optimism is shared, albeit cautiously, by others in the international collaboration.

This experiment "is taking the only modestly successful vaccine trial . . . and trying to improve upon it in a higher-risk population," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which is largely funding the $130 million study with help from the Bill & Melinda Gates Foundation.

If Thembi Dlamini and S'phindile Dlamini pass their health screening, they soon will begin receiving the vaccine or the placebo in a brightly lit clinic in a stout brick building behind a funeral parlor on this town's main strip. All participants will be reminded of the best practices for avoiding the virus, and anyone who becomes infected during the trial will be referred for treatment.

For many, their motivation is the possibility that they could be part of an effort that helps turn the tide.

"I don't want to lose another member of my family," Thembi Dlamini said. "I want to be one of the ones who helped prevent this thing for the future."

Brown reported from South Africa, and Bernstein reported from Washington.