Scientists Find New Receptor for H.I.V.

Scientists Find New Receptor for H.I.V.

Government scientists have discovered a new way that H.I.V. attacks human cells, an advance that could provide fresh avenues for the development of additional therapies to stop AIDS, they reported on Sunday.

The discovery is the identification of a new human receptor for H.I.V. The receptor helps guide the virus to the gut after it gains entry to the body, where it begins its relentless attack on the immune system.

The findings were reported online Sunday in the journal Nature Immunology by a team headed by Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases.

For years, scientists have known that H.I.V. rapidly invades the lymph nodes and lymph tissues that are abundant throughout the gut, or intestines. The gut becomes the prime site for replication of H.I.V., and the virus then goes on to deplete the lymph tissue of the key CD4 H.I.V.-fighting immune cells.

That situation occurs in all H.I.V.-infected individuals, whether they acquired the virus through sexual intercourse, blood transfusions, blood contamination of needles and syringes, or in passage through the birth canal or drinking breast milk.

The findings appear to provide some, if not the main, answers to how and why that situation occurs.

Dr. Warner C. Greene, an AIDS expert and the director of the Gladstone Institute of Virology and Immunology here who was not involved in the research, said the findings were “an important advance in the field.”

“They begin to shed light on the mysterious process on why the virus preferentially grows in the gut,” Dr. Greene said in an interview.

Dr. Fauci, James Arthos, Claudia Cicala, Elena Martinelli and their colleagues showed that a molecule, integrin alpha-4 beta-7, which naturally directs immune cells to the gut, is also a receptor for H.I.V. A protein on the virus’s envelope, or outer shell, sticks to a molecule in the receptor that is linked specifically to the way CD4 cells home in on the gut, the researchers said.

Binding of the virus to the integrin alpha-4 beta 7 molecule stimulates activation of another molecule, LFA-1, which plays a crucial role in the spread of the virus from one cell to another. The actions ultimately lead to destruction of lymph tissue, particularly in the gut.

Several other receptor sites for H.I.V. are known. The most important is the CD4 molecule on certain immune cells; the molecule’s role as an H.I.V. receptor was identified in 1984.

Two other important receptors, known as CCR5 and CXCR4, were identified in 1996. CCR5 is a normal component of human cells and acts as a doorway for the entry of H.I.V. People who lack it because of a genetic mutation rarely become infected even if they have been exposed to H.I.V. repeatedly.

“The work we did took nearly two years, and there’s little doubt that what we have found is a new receptor,” Dr. Fauci said in an interview after giving a lecture here, adding that “we certainly have to learn a lot more about it.”

Scientists have sought to identify receptors because they offer targets for the development of new classes of drugs.

For example, last year the Food and Drug Administration approved for AIDS treatment a Pfizer drug, Selzentry or maraviroc, which works by blocking CCR5.

Dr. Fauci said he hoped his team’s findings would encourage other scientists from different disciplines to explore new ways to attack H.I.V.

A number of experimental drugs that block the integrin alpha-4 beta-7 receptor are being tested for the treatment of autoimmune disorders. Dr. Fauci said such drugs should also be studied for their potential benefit in AIDS treatment.

Organization of new trials in the next year or so could test such drugs in animals and humans to determine their safety and effectiveness against H.I.V., Dr. Fauci said.

One candidate is a drug, Tysabri or natalizumab, that is marketed for treatment of multiple sclerosis, Dr. Fauci said. Biogen/Elan makes Tysabri.

If trials for H.I.V. are successful, Dr. Fauci said, the drugs could be added to existing treatment regimens.

When Incest Is Best: Kissing Cousins Have More Kin

When Incest Is Best: Kissing Cousins Have More Kin

Study analyzing more than 200 years of data finds that couples consisting of third cousins have the highest reproductive success

 
RELATIVE SUCCESS: Scientists find that third and fourth cousins, when they mate, produce more offspring than more closely related couples, as well as distant ones.

It is not quite incest. And though it will increase your chances of birthing a healthy baby, it is a bit unorthodox, to say the least. Still, scientists at Icelandic biotechnology company deCODE genetics say that when third and fourth cousins procreate, they generally have scads of kids and grandkids (relative to everyone else).

It has long been wondered exactly how kinship influences reproductive success. Previous studies have uncovered positive correlations, but the biological data has been clouded by socioeconomic factors (such as average marrying age and family size) in those populations in which consanguineous marriage is commonplace, such as in India, Pakistan and the Middle East. The new study, however, was able to shed light on the biological reason for the earlier findings.

Scientists came to their conclusions after studying the records of more than 160,000 Icelandic couples with members born between 1800 and 1965. "The advantage of using the Icelandic data set lies in this population being small and one of the most socioeconomically and culturally homogenous societies in the world," the researchers report in Science, "with little variation in family size [and] use of contraceptives and marriage practices, in contrast with most previously studied populations."

The results of the exhaustive study are constant throughout the generations analyzed. Women born between 1800 and 1824 who mated with a third cousin had significantly more children and grandchildren (4.04 and 9.17, respectively) than women who hooked up with someone no closer than an eighth cousin (3.34 and 7.31). Those proportions held up among women born more than a century later when couples were, on average, having fewer children.

Despite the general pattern for reproductive success favoring close kinship, couples that were second cousins or more closely related did not have as many children. The most likely reason, scientists say: offspring of such close relatives were likely to have much shorter life spans, because of the chance of inheriting harmful genetic mutations.

"With close inbreeding—between first cousins—there is a significant increase in the probability that both partners will share one or more detrimental recessive genes, leading to a 25 percent chance that these genes will be expressed in each pregnancy," says Alan Bittles, director of the Center for Human Genetics at Edith Cowan University in Joondalup, Australia, who was not involved in the study.

Interestingly, one evolutionary argument for mating with a relative is that it might reduce a woman's chance of having a miscarriage caused by immunological incompatibility between a mother and her child. Some individuals have an antigen (a protein that can launch an immune response) on the surface of their red blood cells called a rhesus factor—commonly abbreviated "Rh." In some cases—typically during a second pregnancy—when a woman gets pregnant, she and her fetus may have incompatible blood cells, which could trigger the mother's immune system to treat the fetus as a foreign intruder, causing a miscarriage. This occurrence is less probable if the parents are closely related, because their blood makeup is more likely to match.

"It may well be that the enhanced reproductive success observed in the Iceland study at the level of third [and] fourth cousins, who on average would be expected to have inherited 0.8 percent to 0.2 percent of their genes from a common ancestor," Bittles says, "represents this point of balance between the competing advantages and disadvantages of inbreeding and outbreeding."

 

Where is the AIDS Vaccine?

Where is the AIDS Vaccine?

Science gets closer, but a fully effective vaccine against HIV remains elusive

 
Despite two decades of work, researchers have not been able to create a satisfactory vaccine against Hiv.

 

Ten years ago President Bill Clinton set a national goal to develop an AIDS vaccine within a decade. At that time, the human immunodeficiency virus (HIV) that causes AIDS had infected some 25 million people worldwide. Clinton established a research center at the National Institutes of Health and pledged to enlist other nations in the effort.

“There are no guarantees,” he said in a speech delivered at Morgan State University announcing the initiative. “It will take energy and focus and demand great effort from our greatest minds. But with the strides of recent years, it is no longer a question of whether we can develop an AIDS vaccine, it is simply a question of when.”

Infectious disease experts cautioned that the goal was overly optimistic. They were right. Today there is still no vaccine, despite an increasingly organized global effort and the quadrupling of funds committed to it. “We have learned in that period of time how formidable an adversary HIV is,” says Wayne Koff, senior vice president for research and development at the International AIDS Vaccine Initiative (IAVI).

The vaccine search suffered its latest disappointment in September, when investigators called an early stop to a clinical trial of a much anticipated new type of HIV vaccine. Like many other candidates now in testing, it was designed to coax the immune system’s disease-killing T cells into attacking the virus more aggressively. Experts say that such a vaccine is unlikely to prevent HIV infection. But they hope at least one candidate will weaken the virus enough to delay the complications of AIDS and to reduce the need for expensive antiretroviral drugs.

Increased funding and more sophisticated organization have played a key role in getting the project this far. “By the early to mid-1990s the AIDS vaccine effort was relatively moribund,” says IAVI president Seth Berkley, who founded the group in 1996. “It’s 100 percent a scientific problem; however, without an enabling environment, you can’t solve the science.”

Global spending for HIV vaccine research increased from $186 million in 1997 to $759 million in 2005, according to the Joint United Nations Program on HIV/AIDS. The IAVI helped to move the field forward by establishing research consortia so that investigators could more easily coordinate and exchange information. The group partnered with governments and vaccine makers to conduct trials outside the U.S., which account for nearly half of the 30-plus trials currently in progress. The NIH formed its own HIV vaccine trial network in 2000 to oversee clinical research sites in the U.S., Africa, Asia, the Caribbean and South America.

The scale of the effort reflects the scientific challenges. In the early 1980s, after identifying the HIV virus as the cause of AIDS, researchers were at first confident that they could come up with a vaccine against it within a few years, Koff says. Vaccines work by exposing the body to a disease-causing agent or a fragment of it. That exposure primes the immune system to produce a flood of antibodies that stick to the infecting organism and block it from entering cells. Researchers identified a protein on the surface of HIV, dubbed gp120, that enables the virus to infect and then slowly destroy so-called helper T cells, which regulate immune responses. The gp120 protein seemed like a good candidate for an HIV vaccine.

And early tests of a gp120 vaccine looked promising. But optimism faded by the early 1990s as researchers learned the vaccine worked only against strains of HIV that had adapted to conditions in the laboratory. In 2003 results finally came in from a phase III clinical effectiveness trial of a gp120 vaccine manufactured by VaxGen: it failed to prevent infections or reduce the number of virus particles circulating in the blood. (A related vaccine, VaxSyn, based on the gp160 protein [see illustration at left], never progressed to late-stage clinical testing.)

By then, HIV researchers had turned to a different idea for a vaccine. They inserted segments of HIV genes into the DNA of partially disabled non-HIV viruses. The resulting viruses could deliver the HIV genes into cells without causing a lethal infection. Infected cells would produce and display HIV proteins, however—thereby energizing the immune system’s T cells to attack those proteins wherever they might appear.

Merck, along with the federally funded HIV Vaccine Trials Network (HVTN), initiated a phase II clinical proof-of-concept trial in late 2004 to quickly study the effectiveness of its adenovirus-based vaccine containing three HIV genes. In September a peek at the data revealed that participants injected with the vaccine had contracted HIV no less often than had those receiving a sham. Investigators halted the study, which had enrolled 3,000 people in the Americas and Australia, as well as a second trial begun in 2006 in South Africa. In the coming months, researchers hope to figure out why the vaccine failed and how to improve the remaining crop.

Next up for rapid testing is a broader-spectrum vaccine developed by the NIH’s Vaccine Research Center (VRC). Sanofi-Aventis is conducting a phase III clinical trial in Thailand of its product, which combines a canarypox virus vaccine with VaxGen’s gp120 vaccine. Results are due as early as 2008.

“The immune response and the safety so far have put these out there further than the other candidates we have,” says disease specialist Scott Hammer of Columbia University, part of the team designing the VRC vaccine trial.

Studies in monkeys seem to support the concept, says immunologist David Watkins of the University of Wisconsin–Madison. Watkins and his colleagues reported in 2006 that rhesus monkeys injected with four genes from the simian immunodeficiency virus—which causes an AIDS-like disease in monkeys and apes—were no less susceptible to infection by the identical strain of the simian virus than were unvaccinated monkeys, but they did maintain lower levels of virus in their blood for up to a year after infection. Another group reported that vaccinated monkeys were more likely to survive three years after infection than unvaccinated animals were. “That was pretty encouraging,” Watkins says. But he cautions against putting too much weight on the early results.

The ability of HIV to mutate rapidly remains one of the biggest obstacles to a successful vaccine. Its genetic material is prone to errors during duplication and replicating HIV molecules frequently exchange pieces of genes. Because of this instability and the potentially rapid life cycle of the virus, the genetic sequences of HIV particles in a single person can be as diverse as those of all the influenza viruses in the world. A vaccine that produces an immune response against one HIV sequence may have no effect on other strains.

To address this problem, the VRC vaccine contains three variants of the HIV envelope gene—the gene that most readily mutates to resist treatment. The HVTN began a second trial of Merck’s vaccine last February in South Africa, where the circulating virus differs from the one on which the vaccine is based.

T cell–stimulating vaccines may help destroy cells infected with HIV, preventing them from reproducing. But experts say they probably would not trigger the immune system to make antibodies and would therefore be only partially effective. “You’re trying to control replication, not prevent infection,” Watkins says. “Although, who knows? Maybe a T cell vaccine could do that.”

Merck and the HVTN called their test “STEP,” because a successful T cell vaccine would be only a step toward full protection—but it could be a highly significant one. The IAVI estimates that even a 30 percent effective vaccine given to just 20 percent of those at risk would avert 5.5 million infections worldwide between 2015 and 2030—or 11 percent of all estimated new infections for that period. A 70 percent effective vaccine administered to twice as many patients could avert 28 million infections.

Still, there are no guarantees. “We should never assume that what we have is going to work,” says Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition in New York City. “We’ve got some very good candidates,” the IAVI’s Berkley adds, “and if they work it’s going to be about access” for developing countries. “We have to make sure there’s going to be the political and financial commitment to drive this effort forward, no matter the results of these trials.”

In the future, researchers hope to find new candidates for antibody vaccines. A few people, when infected with HIV, spontaneously generate antibodies that can fend off the virus for decades. Researchers are studying the structure of these natural molecules. The IAVI established its neutralizing antibody consortium in 2002 to speed the discovery of triggers that would prod the immune system to generate more of them.

After 10 years of research, experts are in a better position to judge their expectations for the future. The consensus: a fully effective AIDS vaccine is a long way off. “There are people who will tell you we will never have a vaccine—I can’t say those people are wrong,” Hammer says. But he adds that “you shouldn’t be in this business if you don’t have some degree of optimism based on the science. The world needs an AIDS vaccine. To give up now is selling the science short.”

The Key to Great Sax

The Key to Great Sax

Pro saxophonists contort their vocal tracts to climb the upper registers

 
 

 

Amateur saxophonists of the world have long been in awe of the piercing high notes jazz legend John Coltrane used to hit, wondering why they can't scale the same auditory heights. Now researchers say they have the answer: Unlike amateurs, pro sax players have learned to flex their vocal tracts in a special way to amplify the high notes.

A sax's sound comes from a flexible reed in the mouthpiece that controls the airflow and pressure through the instrument, setting up strong air vibrations or resonances if a player blows the right way. Musicians and scientists have debated the role of the player's vocal tract—the hollow from the mouth to the glottis (the space between the vocal cords). Some contended that saxophonists have to shape their vocal tracts with their tongues and jaws to create a matching resonance.

"It would make sense for the vocal tract to influence your overall sound, because sometimes just by listening to how somebody plays a line you can tell who it is," says acoustician Jer Ming Chen of the University of New South Wales in Sydney, Australia. But until now, he says, there has been no way to directly measure the acoustics of a vocal tract in mid-note without interfering with the player's sound.

To make a direct measurement, Chen and two of his colleagues in Sydney modified the mouthpiece of a tenor saxophone. They added a device that would emit a combination of 224 tones into the vocal tract of the player, simultaneously recording the intensities of the tones as they bounced back into the mouthpiece, from which they could deduce the vibrations in the tract.

The team recorded five professional and three amateur saxophonists as each played a scale on the modified sax. All players could sound notes below the high, or altissimo, range. For those pitches, there was no strong relationship between resonances in the vocal tract and instrument. Only the pros, however, could break into the altissimo, where a clear relationship emerged: The resonance of the players' vocal tracts was right around that of the note they were playing, the researchers report in Science.

The effect is to amplify the sound of the high notes, which are naturally weak in the sax, Chen says.

But are the pros born with it? Chen thinks not. "They all [said that] to produce the high note at will, they have to think of the note in their head." He takes that to imply a learned relationship born of long, painful hours of practice—which, as we all know, makes perfect.

Toys that Teach, but Turn Parents into Big Brother

Toys that Teach, but Turn Parents into Big Brother

LeapFrog toys allow parents to monitor kids' smarts via the Web

 
CUSTOMIZABLE HANDHELD: LeapFrog's Didj is designed to appeal to the fans of handheld gaming devices.

 
STORY TIME: The Tag reading system identifies optical patterns on a page that allow it to recognize letters and words and read aloud.

When it comes to parental inquiries about school, children generally respond with a shrug and, if they're lucky, an obligatory "nothing." Parents, of course, know better, and will soon be able to track their kids' abilities and smarts thanks to LeapFrog Enterprises, Inc., the Emeryville, Calif., manufacturer of technology-based learning aids.

LeapFrog this week announced its new "Learning Path" strategy, which includes Web-based programs designed to guide children through the company's extensive lineup of devices for developing reading, math and other skills. Learning Path enables parents to use the Web to follow their kids' performance, download new games to LeapFrog devices as well as communicate with educators and even other parents through a community site.

Each time a child finishes playing with one of LeapFrog's USB-enabled toys—including the new Tag reading device or Didj handheld gaming system—parents will be able to view the results by connecting the toy to their PC or Mac and visiting the company's Learning Path site, set to go live in May. The site will reveal the games that each child plays, the number of times he or she plays them, and the skills they're designed to teach. It will also suggest activities tailored to individual kids' needs (for example, having children with trouble reading pick out particular letters or words on different food packages during trips to the supermarket).

The Learning Path Web site, as with all of LeapFrog's products, was designed using the company's proprietary "scope and sequence" methodology, created by its team of curriculum designers in conjunction with the company's 10-member educational advisory board. Scope and sequence, the company says, focuses on identifying what children learn as well as how and when they learn it, including their ages and stages of development. The advisory board includes Anne Cunningham, an associate professor at the University of California, Berkeley, Graduate School of Education; Cathie Norris, a regents professor at the University of North Texas College of Education's Department of Learning Technologies, in Denton, Texas; and Jeni Leta Riley, head of the School of Early Childhood and Primary Education for the Institute of Education, University of London.

As with many things these days, though, this program walks a fine line between learning and privacy. On one hand, it enables parents to play an active role in enhancing their youngsters' education and, also, in keeping tabs on how they are spending their time, allowing them to identify potential trouble spots. But it also opens the door to parents becoming more like "Big Brother," potentially irking kids and discouraging them from using the products. (Any child who understands this reference, by the way, probably doesn't need the Leapfrog learning aids.)

The Didj system resembles the PlayStation Portable (at about half PSP's $170 price tag) and is designed to appeal to kids age six to 10. Using LeapFrog's Connect software and a USB cable, kids can use a computer to create their own game avatars; parents can customize the game's educational curriculum (specifying an emphasis on certain math skills or a particular spelling list), and then load all of this information onto the handheld device. The Didj, which hits the stores in July, runs on a 393 megahertz Arm 9 processor and features 32 megabytes of RAM, 256 megabytes of flash storage and a 3.2-inch (8.1-centimeter) LCD screen.

The Tag reading system, which debuts in June priced at $50, borrows from the company's FLY Fusion Pentop Computer (minus the handwriting-recognition capabilities) to provide an exclamation point–shaped handheld device that reads when its tip is touched against words in one of LeapFrog's children's books. Using an optical pattern system and digital processing techniques licensed from Sweden's Anoto Group, AB, the Tag reader can determine the precise location in any given book and any page as well. The device features a 32-bit computer processor as well as LeapFrog's proprietary operating system and software.