HIV Vaccines Elicit Immune Response in Infants

A new analysis of two HIV vaccine trials that involved pediatric patients shows that the investigational vaccines stimulated a critical immune response in infants born to HIV-infected mothers

The finding at the AIDS Vaccine 2013 meeting in Barcelona, Spain, examined samples from two previously completed pediatric HIV vaccine trials - called PACTG 230 and PACTG 326 - to determine whether they elicited a key immune response that has only recently been associated with reduced HIV infection.

Searching for evidence of an anti-V1V2 IgG antibody response - the newly identified mechanism for protection against HIV - the researchers found that both of the old pediatric vaccine candidates triggered this key immune defense. While babies born to HIV-infected mothers had maternally acquired anti-V1V2 IgG antibodies at birth, infants who were vaccinated had better and longer-lasting antibody responses than their counterparts who received a placebo vaccine.

"Effective infant HIV vaccination may be affected by the presence of maternal HIV-specific antibodies and the immaturity of the infant immune system," said the study's lead author, Genevieve Fouda, M.D., PhD, of Duke. "Our findings suggest that vaccination of infants born to HIV-infected mothers can elicit a robust anti-HIV envelope IgG immune response."

Fouda said the results of the study highlight the importance of including pediatric populations in HIV vaccine studies. "Mother-to-child transmission continues to be an important public health issue in resource limited areas," Fouda said. "Every year, approximately 300,000 infants are infected with HIV. Antiretroviral drugs have reduced the rate of mother to child transmission rate in the United States below 2 percent, but overall in low and middle income countries less than 60 percent of known HIV infected women receive drugs to prevent transmission to their infants. Immune-based interventions such as a vaccine are needed to eliminate pediatric HIV."

Anabolic steroids help people with HIV put on weight and muscle mass

People with HIV who are treated with anabolic steroids to prevent AIDS wasting may realize modest gains in weight and muscle mass.

The review covered 13 studies of adults age 24 to 42 with HIV, 294 of whom received anabolic steroids for at least six weeks and 238 of whom received placebo. The average weight increase in those taking anabolic steroids was nearly three pounds.

“The magnitude of weight gain observed may be considered clinically relevant,” said lead author Karen Johns, a medical assessment officer from the agency Health Canada. “One hopes there would be greater weight gain with the long-term use of anabolic steroids; however, this has not been proven to date in clinical trials.”

AIDS wasting, which leads to significant weight loss in people with HIV, causes severe loss of weight and muscle and can lead to muscle weakness, organ failure and shortened lifespan. Researchers have long sought to reverse this common, destructive effect of HIV with mixed success.

The wasting stems from loss of the body’s ability to grow muscle and from low levels of testosterone.

Anabolic steroids are synthetic substances similar to the male sex hormone testosterone that promote growth of skeletal muscle and the development of male sexual characteristics.

Although most recently in the news for their misuse by professional athletes, anabolic steroids have legitimate medical application for men with low testosterone and people with certain types of anemia. Two anabolic steroids available in the United States, nandrolone decanoate and stanozolol, have been used to help increase weight and muscle mass in small studies of people with wasting.

Conversely, anabolic steroid use has been associated with increased rates of HIV in those who share needles or use nonsterile needles when they inject steroids.

In the review studies, anabolic steroids were administered to patients either orally or by injection. The main side effects were mild and included abnormal liver function tests; acne; mild increase in body hair; breast tenderness; increased libido, aggressiveness and irritability; and mood swings — all common side effect of anabolic steroid use.

“The risks and side effects of taking anabolic steroids long-term are certainly of concern,” Johns said. “We were unable to assess these risks in our review due to the short duration of treatment in the studies.”

Wayne Dodge, M.D., the HIV/AIDS program director at the Group Health Cooperative in Seattle, suggests that clinicians should obtain blood testosterone levels, “if an HIV-infected individual has had significant weight loss, significant fatigue or muscle wasting, and particularly if associated with a significant decrease in libido and erections. If [testosterone] is in the low or low-normal range then a trial of [steroids] could be tried. The individual and the clinician should decide what result would constitute a successful trial: weight gain of 15 pounds, a 30 percent improvement in sense of well-being [or] a successful erection once a week.”

The reviews authors conclude that further studies are needed to determine if increase in weight leads to improved physical functioning and quality of life, and ultimately increased survival, as well as the potential for serious side effects, especially with prolonged use.

Barriers to HIV Vaccine Response Explored

Researchers at The Scripps Research Institute (TSRI) discovered that an antibody that binds and neutralizes HIV likely also targets the body's own "self" proteins. This finding could complicate the development of HIV vaccines designed to elicit this protective antibody, called 4E10, and others like it, as doing so might be dangerous or inefficient.

"We developed two new mouse models that allow us to visualize the fate of the rare B cells that can see HIV and we thought could be stimulated by vaccines to produce neutralizing antibodies -- the type of antibodies we seek to produce in response to a vaccine," said David Nemazee, PhD, professor in the Department of Immunology and Microbial Science at TSRI and senior author of the study. "We were able to study vaccine responses of b12, an antibody that sees the CD4 binding site of HIV, but, surprisingly to us, not 4E10, an antibody that sees the stem of the HIV envelope protein."

Nemazee and his team went on to discover that cells with the potential to produce 4E10 antibodies trigger several natural safeguards that shut down the production of any antibody that might recognize and destroy the body's own tissues. They concluded that 4E10 cross-reacts with host tissues in this way, prompting its removal before it can do any harm - or good.

HIV Vaccine Development

4E10 antibodies were originally isolated from a human HIV patient. The antibodies specifically recognize and bind an HIV surface protein called gp41. The virus uses gp41 like a long spike to poke holes in its host's immune cells. But when 4E10 antibodies clog up gp41, the virus is neutralized and host cells are protected.
4E10 especially interests HIV researchers because the antibody recognizes and binds to gp41 on the surface of many different strains of the virus, not just the one strain with which the patient was most recently infected. If a vaccine could be made to specifically and safely stimulate 4E10-like production, recipients would likely be protected against multiple HIV strains.

In humans, HIV slowly destroys the immune system, leading to Acquired Immune Deficiency Syndrome (AIDS). According to the Centers for Disease Control and Prevention, more than 1.1 million people in the U.S. are living with HIV infection. While treatments developed in the past decade can keep the virus in check for many years, there is no vaccine and there is no cure.

Proceeding with Caution

In several ongoing studies, the TSRI team and others are working out how to make a vaccine that stimulates the production of 4E10, b12 and other broadly neutralizing anti-HIV antibodies. However, this latest study indicates that this approach might be complicated by unwanted self-reactivity. Antibodies that cross-react with host tissue -- like 4E10 has now been shown to do -- are associated with autoimmune diseases such as multiple sclerosis and lupus.
The TSRI study also raises the question of how 4E10 was generated in the first place. According to Nemazee, 4E10 may be a fluke, cropping up in an HIV patient who was also prone to autoimmune diseases. Alternatively, the autoreactive antibody could have arisen in the patient as a consequence of the disease -- perhaps the body's normal mechanism for weeding out such antibodies failed, allowing the serendipitous production of an anti-HIV antibody.

Despite this new concern, there is still hope for 4E10's role in HIV vaccine development. A companion paper published in the same issue of The Journal of Immunology (http://www.jimmunol.org/content/191/6/3179.long) found that another potent, broadly neutralizing anti-HIV antibody, b12, was not self-reactive and could respond to a candidate vaccine preparation provided by Richard Wyatt, TSRI Professor of Immunology and Director of Viral Immunology at the International AIDS Vaccine Initiative Neutralizing Antibody Center.

"It's still possible that we could safely elicit the 4E10-like antibody in order to protect against HIV," Nemazee said. "We just have to think about how to generate the best antibodies without causing other problems. We have a lot of questions. And now we have a good model to help us answer them."

Man cured of AIDS after receiving stem cell transplant

In what many in the mainstream media and medical community have now dubbed their first known case of cured AIDS, Timothy Ray Brown's miraculous healing from the deadly syndrome is sending shock waves throughout the world. After receiving a bone marrow stem cell transplant back in 2007, Brown inherited a genetic immunity from those stem cells that cured him of not only AIDS, but also leukemia.

Dubbed "The Berlin Patient," Brown first tested positive for HIV back in 1995. And for years, he unsuccessfuly battled the disease using conventional methods. But when doctors decided to give him a stem cell transplant, everything changed.

"I quit taking my HIV medication the day that I got the transplant and haven't had to take any since," said Brown to reporters from CBS 5 in San Francisco. "I'm cured of HIV. I had HIV, but I don't anymore."

According to reports, roughly one percent of Caucasians have a natural immunity to HIV and AIDS, and the stem cells Brown received came from someone within this rare one percent. As a result, the white blood cells created in his body via the injected stem cells ended up giving him that same immunity.

Brown's doctors, as well as various other experts and scientific journals, have all confirmed that Brown has been cured of both his AIDS and his leukemia. And Dr. Judy Auerbach from the San Francisco AIDS Foundation told CBS reporters that "things have shifted" in terms of using the word "cure" in reference to AIDS, which is breathing new hope into those hopeful for a cure themselves.

However, despite the numerous references in the media to Brown being the first person ever to have been cured of AIDS, there have actually been many others who have successfully defeated the syndrome through immune support -- but these cases, of course, have been ignored by the mainstream medical and scientific community. In fact, a healthy immune system is the true key to both resisting HIV infection, and successfully reversing it. 

HIV: Predicting Treatment Response More Accurately

The HI virus is feared, not least, because of its great adaptability. If the virus mutates at precisely the point targeted by a drug, it is able to neutralise the attack and the treatment fails. To minimise these viral defence mechanisms, doctors treat patients with modern combination therapies involving the simultaneous administration of several drugs. This approach forces the virus to run through a series of mutations before it becomes immune to the drugs.

"It is not easy to decide which of the over 30 combination therapies is best suited to a patient," says Huldrych Günthard from Zurich University Hospital, president of the Swiss HIV Cohort Study. The decision is based on the prospects of success and therefore on the genetic make-up of a particular virus. The established prediction models already consider the genetics of the virus but they neglect that the virus continuously evolves through sequential mutations.

Choosing the right therapy for each patient

In cooperation with the Swiss HIV Cohort Study, Niko Beerenwinkel and his team from ETH Zurich have now developed a more accurate prediction model based on a probabilistic method. This model calculates the possible evolutionary paths of the virus and yields a new predictive measure for the development of resistances: the so-called individualised genetic barrier. When applied retrospectively to 2185 patients of the HIV Cohort, the new approach made it possible to predict treatment success more accurately compared to the existing models. "We are now introducing the individualised genetic barrier in a pilot project and hope that it will help us in the future to identify the best therapy for each patient," says Günthard.

Preventive Antibiotics for Tuberculosis Reduce Deaths Among People With HIV Disease

The research team's findings, stem from what is believed to be the largest expansion of a clinic-based, community health program designed to curb the spread of TB, and the first evidence that such a community-wide effort can be highly effective at preventing people who are co-infected from developing active TB disease.

According to senior study investigator and Johns Hopkins infectious disease specialists Richard Chaisson, M.D., his team's latest study results firmly support broad use of preventive isoniazid therapy for millions of people infected with HIV in Latin American, Asian, and Eastern European countries heavily burdened by TB.

Chaisson says TB disease remains the leading cause of death worldwide among those with HIV/AIDS and is epidemic in developing countries with the highest HIV-infection rates. Isoniazid treatment, which costs less than $1 for a full course of therapy, is already recommended by the World Health Organization to prevent TB in people with HIV disease. The policy, however, has not been widely adopted and its broad impact on the HIV-infected community never shown until the Johns Hopkins and Brazilian team's latest study.
All of the 12,816 study participants were eligible for screening for TB infection or active TB disease. Some 1,186 tested positive for TB infection, but did not have symptoms of TB sickness and could start taking 300 milligrams of isoniazid daily for six months. All received routine follow-up care for as little as a few weeks to as long as four years after initially seeking treatment at any of 29 HIV clinics across Brazil, a country hit hard by both infectious diseases. Some 838 deaths occurred during the study, which took four years to complete, and 475 developed TB. Symptoms of active TB disease, indicating the disease has progressed from latent infection, include persistent cough, chest pain, chills, fever, muscle weakness and fatigue.
"Our study results show that routine testing for TB and preventive isoniazid therapy works well at the community level in people with HIV disease in curbing the spread of TB and lowering the number who die," says Chaisson, a professor at the Johns Hopkins University School of Medicine and founding director of its Center for Tuberculosis Research.

"People with HIV disease living in all countries with rampant TB should be asking their physicians if they are good candidates for preventive isoniazid therapy," says Chaisson, who leads the overall global research effort, in support of this study and others, called the Consortium to Respond Effectively to the AIDS/TB Epidemic. CREATE, as it is known, is funded by the Bill and Melinda Gates Foundation.
When researchers restricted their analysis to 12,196 study participants who kept at least one annual check-up appointment, the overall death rate and number of new TB cases was even lower, at 55 percent. The number of active TB cases decreased by 58 percent. Among study participants who received isoniazid, commonly marketed under the brand names Niazid, Laniazid and Nydrazid, 85 percent took a full course of drugs for six months, as prescribed.

Another important finding, researchers say, was that initial TB screening of those seeking HIV care led to diagnosis of over a third (34 percent, or 250) of the total 725 new clinic patients found to have active TB. All were offered treatment for their disease but were excluded from the study analysis.

Lead study investigator and Johns Hopkins epidemiologist Jonathan Golub, Ph.D., M.P.H., says the study was, on its own, an effective screening tool, and affirms how unknown TB cases can be found when public health officials focus on community health programs in local clinics that service people more likely to become infected. In Brazil, an estimated 10 percent of people diagnosed with TB sickness are co-infected with HIV.
Golub says further research is needed to determine how long lasting are isoniazid's protective effects are and whether the single course of treatment used in the latest study is sufficient, or if repeat or lifelong antibiotic therapy is needed to suppress TB.

"Our efforts highlight the importance of continuous training in diagnosing TB, and our immediate priority is to train community doctors and nurses in HIV clinics to make TB testing part of routine HIV care," says Golub, an associate professor at Johns Hopkins. Golub points out that in Brazil, TB screening policies have been in place since 1995, but simply not followed. Golub says that once clinics involved in the study began more rigorous screening, the number of initial TB skin tests performed jumped threefold, and the number of patients taking isoniazid went up fourfold.

For the study, clinic staff were rigorously trained in correct procedures for screening all patients with HIV for possible TB infection and signs of active TB disease. Patients who tested positive for active TB disease were offered treatment, but were not included in study monitoring. Those who met study criteria were offered preventive isoniazid therapy. To detect TB, a simple skin test is initially performed, which if positive for signs of an immune response, can lead to further, confirmatory lab and X-ray testing.

Intensive training at all 29 clinics was randomly staggered every two months, allowing staff at all clinics to eventually benefit from the enhanced study effort. The staggered timeline also gave researchers a long period to assess isoniazid's effects pre- and post-training. Study participants were 61 percent male, and on average 37 years old. Sixty percent were receiving antiretroviral therapy for HIV.

Chaisson says the team next plans to evaluate faster diagnostic tests for TB, other than the initial skin test, which takes only minutes to administer, but requires a 48-hour waiting period to show any reaction. He says the ideal test would be a blood test that could be performed at the same time as routine anti-HIV tests for blood levels of CD4 immune cells.

Brain functioning in HIV-infected adults improved by Exercise

Regular exercise is not only good for health, but can give people living with HIV a significant mental boost. This is according to a study by Dr. David J. Moore and colleagues at the University of California, San Diego (UCSD)

The study found that HIV-infected adults who exercise suffered significantly less neurocognitive impairment compared to patients who do not exercise.

Moore and his team, including UCSD medical student Catherine Dufour, found that HIV-infected adults who exercise were approximately half as likely to show signs of neurocognitive impairment as compared to those who do not. They also had better working memory and could process information faster than patients who follow a sedentary lifestyle.

Despite recent advances in antiretroviral treatment, impaired brain functioning is a reality faced by nearly half of all people living with HIV. This ranges from asymptomatic neurocognitive impairment, to more pronounced deficits that interfere with daily functioning, such as problems with financial management, driving and taking medication regularly.

The major benefit of exercise to the brain seems to be the reduction of neurocognitive risk factors, such as high blood pressure and abnormally high levels of lipids in the blood. Metabolic syndrome associated with the use of antiretroviral treatment is also linked to an increase in cerebrovascular risk factors, such as diabetes, hypertension and obesity.

In the study, 335 community-dwelling HIV-infected people were asked how much exercise they undertook during the previous 72 hours, and persons were classified into those who engaged in significant exercise (e.g., activities that make the heart beat rapidly) and those who did not. Seven cognitive areas commonly affected by HIV were tested, including verbal fluency, working memory, speed of information processing, learning, recall, executive function and motor function.

The study extends prior findings about the link between exercise and cognition among HIV-infected people by showing that this association is also true in a diverse and large group of people living with the disease. Compounding factors were taken into account, such as demographics, HIV disease characteristics, substance use, past and current depression, mental health status and physical functioning.

"Exercise as a modifiable lifestyle behavior may reduce or potentially prevent neurocognitive impairment in HIV-infected persons," says Moore. "Physical exercise, together with other modifiable lifestyle factors such as education, social engagement, cognitive stimulation and diet could be fruitful interventions to support people living with HIV."

HIV as You Get Older

Many people think of HIV as a young person's disease, but it's not. "By 2015, half of all people with HIV will be 50 or older," says Brad Hare, MD, director of the HIV/AIDS clinic at San Francisco General Hospital. This greying of the HIV population shows how well today’s HIV treatments can work.

HIV makes aging itself more complicated. But plenty of people have had HIV for years, even decades, and are doing well.  "These days, we fully expect that someone with HIV will live a long, healthy life," says Christine A. Wanke, MD, professor of medicine and director of the nutrition and infection unit at Tufts University School of Medicine. "But that means they have to plan ahead and adopt the healthy habits to stay that way, just like anyone without HIV."

HIV and Aging: 5 Common Challenges

As you get older with HIV, you may face issues including:

1. Other conditions. Just like anybody, getting older means you're more likely to have health problems, and HIV seems to bump up the risk even more. "HIV accelerates the aging process and magnifies its effects," says John G. Bartlett, MD, professor at the Johns Hopkins School of Medicine and director of its AIDS service. So HIV may make you more likely to get heart disease, diabetes, cancer, osteoporosis, kidney problems, and other conditions.

2. Drug interactions. Since you’re already taking medicines for HIV, additional drugs for other conditions can increase the chance of interactions.

3. Loss of support. Some people become more isolated as they age. That happens more often to people with HIV, who may also be dealing with embarrassment about the condition or strained family relationships. If you're alone and disconnected, you're more likely to get depressed.

4. Changing roles. Like many people without HIV, you may be caring for your aging parents. That can add emotional and financial pressures.

5. Difficulty adjusting. "I talk to people with HIV who say, 'I didn't expect to live to middle age,'" says Hare. "'But now I'm middle-aged and I'm probably going to live another 30 years.'" Many people who got HIV long ago didn't plan for a long life, and adjusting can be a challenge. For instance, you might not have saved for a longer life.

7 Steps to Take

1. See an HIV expert. The more your health is complicated by age and other conditions, the more crucial it is to have an expert overseeing your HIV care.

2. Get good routine medical care. Specialty HIV care is not enough. Because your risks of other medical problems are higher, keep on top of your general health, says Hare. Get your annual physicals, keep tabs on your blood pressure, cholesterol, and other tests your doctor recommends.

3. Avoid drug interactions. Make certain every doctor you see knows about every medication and supplement you take, including prescription drugs, over-the-counter products, vitamins, and natural products. Doctors may adjust your medicines, dosages, or schedules to prevent interactions.

4. Improve your lifestyle. To enjoy life as you age, stay fit. Exercise regularly, and if you smoke, stop.

5. Eat a healthy diet. Go for lots of fruits and vegetables, lean proteins, whole grains, and healthy fats. "Eating a heart-healthy diet makes sense for everyone," says Bartlett. "But because people with HIV have higher risks of heart disease, it makes even more sense for them."

6. Seek support. Having a support system of family and friends is key. Make an effort to stay connected. If close friends or family have died or moved away, work on making new friends. You might also connect through a support group.

7. Get help. Call your local health department to learn about local resources for people with HIV, says Hare. Your local Council on Aging is a good place to start; it can point you toward programs and services that could help. A financial planner may also help you work on savings and expenses.

Plant-Based Compound May Inhibit HIV

A compound found in soybeans may become an effective HIV treatment without the drug resistance issues faced by current therapies

It's in the early stages, but genistein, derived from soybeans and other plants, shows promise in inhibiting the HIV infection, says Yuntao Wu, a professor with the George Mason-based National Center for Biodefense and Infectious Diseases and the Department of Molecular and Microbiology.

Still, that doesn't mean people should begin eating large amounts of soy products. "Although genistein is rich in several plants such as soybeans, it is still uncertain whether the amount of genistein we consume from eating soy is sufficient to inhibit HIV," Wu says.

Genistein is a "tyrosine kinase inhibitor" that works by blocking the communication from a cell's surface sensors to its interior. Found on a cell's surface, these sensors tell the cell about its environment and also communicate with other cells. HIV uses some of these surface sensors to trick the cell to send signals inside. These signals change cell structure so that the virus can get inside and spread infection.

But genistein blocks the signal and stops HIV from finding a way inside the cell. It takes a different approach than the standard antiretroviral drug used to inhibit HIV. "Instead of directly acting on the virus, genistein interferes with the cellular processes that are necessary for the virus to infect cells," Wu says. "Thus, it makes the virus more difficult to become resistant to the drug. Our study is currently it its early stage. If clinically proven effective, genistein may be used as a complement treatment for HIV infection."

Wu sees possibilities in this plant-based approach, which may address drug toxicity issues as well. Because genistein is plant-derived, it may be able to sidestep drug toxicity, a common byproduct of the daily and lifelong pharmaceutical regimen faced by patients with HIV to keep the disease at bay, Wu says. Typically, patients take a combination of multiple drugs to inhibit the virus. The frequency can lead to drug toxicity. Plus, HIV mutates and becomes drug-resistant.

Wu and his team are working at finding out how much genistein is needed to inhibit HIV. It's possible that plants may not have high enough levels, so drugs would need to be developed, Wu says.

HIV/AIDS Vaccines: Defining What Works

Designing an effective HIV/AIDS vaccine is something of a paradox: a good vaccine would be safe and look enough like HIV to kick-start the immune system into neutralizing the virus -- but the problem is that this is exactly what the human immune system has trouble doing even when it's exposed to the real thing.

Now a team of researchers led by scientists at The Scripps Research Institute in La Jolla, CA has developed a strategy for inducing a key part of an effective immune response to HIV. By tracing the evolution of HIV-recognizing molecules called antibodies taken from the blood of rare individuals whose immune systems are naturally able to target and neutralize the virus, they may have found a way to replicate this for everybody.
At a talk next week at the American Crystallographic Association meeting in Hawaii, the team will present multiple crystal structures, which like detailed architectural blueprints show how the virus interacts with components of the immune system. Examining these structures has allowed them to reverse engineer molecules that specifically activate the precursors of effective, neutralizing antibodies against the virus -- molecules that may be components of a future vaccine against HIV.
"What we tried to do was to learn how those [effective] antibodies developed over the course of natural infection and attempt to guide the immune response in the direction of what we know works in certain HIV-infected individuals," said structural biologist Jean-Philippe Julien, who is presenting the work in Hawaii.
He conducted the research under the direction of Professors Ian Wilson and William Schief of The Scripps Research Institute. The work was funded by the International AIDS Vaccine Initiative Neutralizing Antibody Center, the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and the National Institute of Allergy and Infectious Diseases (one of the National Institutes of Health). Additional support was provided through a Canadian Institutes of Health Research fellowship.
Julien cautioned that the work might not, by itself, be the final answer that shows how to make an effective HIV/AIDS vaccine -- but it is a step in the right direction. Most likely, Julien said, any future HIV/AIDS vaccine would combine multiple biological components in order to give the broadest possible protection against the virus.
He added that their candidate molecule was able to achieve the desired immune reactions in the test tube, and they are currently testing it in animals to see if it is able to kick start the desired immune response. If those experiments go well, he said, further studies will examine whether it can protect animals against infection, and human trials for safety and vaccine efficacy would be next -- though it may be years before those results are known.
While designing a vaccine against any pathogen is a long, hard process, HIV has been particularly difficult, and despite decades of efforts and hundreds of millions of dollars spent in the process, we still do not yet have an effective vaccine that can prevent infection.