Gene Transfer Technology May Lead To HIV Vaccine

A research team may have broken the stubborn impasse that has frustrated the invention of an effective HIV vaccine, by using an approach that bypasses the usual path followed by vaccine developers. By using gene transfer technology that produces molecules that block infection, the scientists protected monkeys from infection by a virus closely related to HIV—the simian immunodeficiency virus, or SIV—that causes AIDS in rhesus monkeys.

"We used a leapfrog strategy, bypassing the natural immune system response that was the target of all previous HIV and SIV vaccine candidates," said study leader Philip R. Johnson, M.D., chief scientific officer at The Children's Hospital of Philadelphia. Johnson developed the novel approach over a ten-year period, collaborating with K. Reed Clark, Ph.D., a molecular virologist at Nationwide Children's Hospital in Columbus, Ohio.

Johnson cautioned that many hurdles remain before the technique used in this animal study might be translated into an HIV vaccine for humans. If the technique leads to an effective HIV vaccine, such a vaccine may be years away from realization.

Most attempts at developing an HIV vaccine have used substances aimed at stimulating the body's immune system to produce antibodies or killer cells that would eliminate the virus before or after it infected cells in the body. However, clinical trials have been disappointing. HIV vaccines have not elicited protective immune responses, just as the body fails on its own to produce an effective response against HIV during natural HIV infection.

The approach taken in the current study was divided into two phases. In the first phase, the research team created antibody-like proteins (called immunoadhesins) that were specifically designed to bind to SIV and block it from infecting cells. Once proven to work against SIV in the laboratory, DNA representing SIV-specific immunoadhesins was engineered into a carrier virus designed to deliver the DNA to monkeys. The researchers chose adeno-associated virus (AAV) as the carrier virus because it is a very effective way to insert DNA into the cells of a monkey or human.

VIA: Sciencedaily

AIDS patients with serious complications benefit from early retroviral use, study shows

HIV-positive patients who don't seek medical attention until they have a serious AIDS-related condition can reduce their risk of death or other complications by half if they get antiretroviral treatment early on, according to a new multicenter trial led by researchers at the Stanford University School of Medicine.

The study results could lead to widespread changes in treatment for HIV patients, particularly those diagnosed at an advanced stage, experts say.

"Even in San Francisco, one of the first epicenters of HIV in the United States, we still find that many people present late in the course of their illness with an opportunistic infection," said Mitch Katz, MD, San Francisco's director of health, who was not involved in the study. "This study shows that it is life-saving to treat those persons with antiretroviral drugs while they are still in the hospital. The results of this study will change practices throughout the world."

Some 60,000 to 70,000 newly HIV-infected individuals are identified every year in the United States, according to recently revised figures from the federal Centers for Disease Control and Prevention. A growing number of these patients, particularly minorities, youth, injection-drug users and those in poor rural areas, are being diagnosed late in the disease process when they've already developed life-threatening conditions, said Andrew Zolopa, MD, associate professor of infectious diseases and geographic medicine at Stanford and first author of the study. When these patients come for treatment of these complications, doctors are often reluctant to give them anti-AIDS drugs at the same time, fearing the two therapies could interfere with one another.

"A lot of people wait, thinking, 'Let's get the patient out of acute crisis, and then we'll deal with the underlying HIV infection later,'" said Zolopa. "But that answer is wrong. If we're more aggressive with HIV drugs, we can reduce AIDS-related complications and death by 50 percent. It's a substantial clinical benefit."

The study was conducted by the AIDS Clinical Trials Group, the world's largest clinical trial organization. Results will be published May 18 in the online journal PLoS-ONE.

William Powderly, MD, dean of medicine at the University College Dublin School of Medicine, said the study addresses one of the last, longstanding unknowns in the management of AIDS.

"Clinicians have long grappled with the question of whether or not early treatment with antiviral drugs will help people who come to the hospital with advanced infections, such as pneumonia," said Powderly, the study's senior author. "The answer is clearly yes. Early antiviral treatment for HIV improves the clinical outcome, including the likelihood of surviving in the next few months. It probably does so by improving the immune system and therefore adds to the ability to resist these infections."

VIA : Physorg

Study shows that HIV antiretroviral treatment should start earlier

A new analysis of more than 45,000 people with HIV in Europe and North America suggests that the minimum CD4-cell count threshold for initiation of combination antiretroviral therapy (cART) should be 350 cells per µL of blood. This is at the upper limit of levels for starting cART currently recommended in many countries.

The findings are published in an article in an upcoming edition of The Lancet, written by Jonathan Sterne, Professor of Medical Statistics and Epidemiology, University of Bristol, and colleagues from the When To Start Consortium of observational cohort studies of people with HIV.

The CD4-cell count at which cART should be started is a central, unresolved issue in the care of HIV-1 infected patients.

In the absence of randomised controlled trials, the authors analysed data from 18 prospective studies from Europe and North America, of which 15 provided eligible patients who had not previously been treated with antiretroviral drugs. Patients were included if they had started cART (while AIDS-free, with a CD4-cell count less than 550 cells per µLm and with no history of injecting-drug use) on or after January 1, 1998. Data from patients followed up in seven cohorts in the era before the introduction of cART were used to estimate the relationship between when treatment started and AIDS related events or death.

Data was obtained for 21,247 patients who were followed up during the era before the introduction of cART and 24,444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4-cell count of 251-350 cells per µL was associated with a 28 per cent higher rate of AIDS and death than starting therapy in the range 351-450 cells per µL. The adverse effect of deferring treatment increased with decreasing CD4-cell count threshold. Deferred initiation of combination therapy in the above ranges was also associated with higher mortality rates (13 per cent), though the effect on mortality was less than the effect on the combined endpoint of AIDS and death.

The authors said: “When patients and their physicians consider starting antiretroviral treatment, they must balance its beneficial effects on rates of progression to AIDS and death with several other issues. Eradication of HIV from an individual is not currently possible; therefore, treatment is expected to be lifelong. Antiretroviral drugs can be inconvenient to take, and have side effects that include nausea, diarrhoea and headache. Combination antiretroviral therapy is associated with serious toxic effects including redistribution of body fat, hepatitis, renal failure and mitochondrial toxicity, and an increased risk of cardiovascular disease. However, these toxic effects are to an extent avoidable through choice of drug regimen.

VIA : Physorg

Scientists Find Rare, Potent Antibody to HIV-1

Scientists at Duke University Medical Center have for the first time isolated an important antibody in human serum that could potentially play a key role in the design of an AIDS vaccine. The research appears as a highlighted feature online in the Journal of Virology.

"The 2F5-like antibody is one of the gold standards for what an HIV vaccine needs to induce, but no one had ever found it before circulating in the blood of infected patients," says Georgia Tomaras, PhD, associate professor of surgery, immunology and molecular genetics and microbiology in the Duke Human Vaccine Institute and the senior author of the study.

The 2F5 antibody is especially valuable because previous research has shown it can successfully neutralize 80 percent of transmitted HIV viruses.

Now that researchers have found the antibody in circulating blood, Tomaras says they might be able to find ways to duplicate or enhance it, thereby boosting the body's defense system.

2F5-like antibodies belong to a class of immune cells called broadly neutralizing antibodies, one of the body's most powerful responses to infection. Only a small fraction of patients with HIV make these antibodies and they typically appear many months after initial transmission of the virus - at a point when scientists feel it is too late to do much good.

Tomaras, working closely with lead author Xiaoying Shen, led a team of researchers who examined the antibodies present in 300 patients infected with HIV-1. They found only one patient who had developed 2F5-like antibodies, supporting the notion that they are, indeed, very rare.

Researchers discovered that the 2F5-like antibody was potent enough to block multiple strains of HIV in the laboratory, but researchers say they are not entirely clear if it played any part in controlling the virus in the patient who carried it.

The scientists were also struck by another discovery: The 2F5-like antibodies arose concurrently with particular autoantibodies that may be a clue as to why these antibodies developed in this person and not in others.

VIA : Physorg

HIV is evolving to evade human immune responses

HIV is evolving rapidly to escape the human immune system, an international study led by Oxford University has shown. The findings, published in Nature, demonstrate the challenge involved in developing a vaccine for HIV that keeps pace with the changing nature of the virus.

‘The extent of the global HIV epidemic gives us a unique opportunity to examine in detail the evolutionary struggle being played out in front of us between an important virus and humans,’ says lead researcher Professor Philip Goulder of the Peter Medawar Building for Pathogen Research at Oxford University.

‘Even in the short time that HIV has been in the human population, it is doing an effective job of evading our best efforts at natural immune control of the virus. This is high-speed evolution that we’re seeing in the space of just a couple of decades.’

HIV has already killed 25 million people, and an estimated 33 million are currently infected. However, HIV does not kill all people at the same rate. On average, an adult with HIV will survive for ten years without anti-HIV drugs before developing AIDS. But some people will progress to AIDS within 12 months while others can make effective immune responses to the virus and survive without any anti-HIV therapy for over 20 years.

Genes encoding a key set of molecules in the human immune system called the human leucocyte antigens (HLA) are critically important. HLA determine the progress of many infectious diseases including HIV, and enable the recognition and killing of HIV-infected cells. Humans differ from each other in the exact HLA genes they have, and small differences can make the difference in how long it takes to progress to AIDS.

The research team set out to determine whether HIV is adapting to human immune responses. They looked at HIV genetic sequences in different countries around the world, including the UK, South Africa, Botswana, Australia, Canada, and Japan, wanting to see whether the HIV sequences could be related to the different HLA genes present in the different populations.

The collaboration between Oxford University, the Ragon Institute at Massachusetts General Hospital, Kumamoto University in Japan, the Royal Perth Hospital and Murdoch University in Australia and others analysed the genetic sequences of the HIV virus and human leucocyte antigen (HLA) genes in over 2,800 people. The work was funded by a number of organisations including the Wellcome Trust, the Medical Research Council, the US National Institutes of Health, and Oxford’s James Martin 21st Century School.

VIA : Physorg