Long-acting drug effectively prevents HIV-like infection in monkeys

The new drug cabotegravir (in vials above) has been shown to protect monkeys from infection by an HIV-like virus, and a clinical trial testing cabotegravir's safety and acceptability has begun. Unlike other preventive treatments, it would require only one injection every three months.
Credit: Zach Veilleux / The Rockefeller University

A regime of anti-HIV drugs -- components of regimens to treat established HIV infection -- has the potential to protect against infection in the first place. But real life can interfere; the effectiveness of this prophylactic approach declines if the medications aren't taken as prescribed.

HIV researchers hope a new compound, known as cabotegravir, could make dosing easier for some because the drug would be administered by injection once every three months. A clinical trial testing long-acting cabotegravir's safety and acceptability has already begun at multiple U.S. sites including The Rockefeller University Hospital. Meanwhile two new studies, including one conducted by researchers at the Aaron Diamond AIDS Research Center (ADARC) and Rockefeller University, published today (January 15) in Science Translational Medicine, show that long-acting cabotegravir injections are highly protective in a monkey model of vaginal transmission of a virus similar to HIV.

"Clinical trial results have demonstrated that the effectiveness of preventive oral medications can range with results as high as 75 percent effective to as low as ineffective, and a lot of that variability appears to hinge on the patient's ability to take the pills as prescribed," says study researcher Martin Markowitz, a professor at Rockefeller University and ADARC. "Long acting cabotegravir has the potential to create an option that could improve adherence by making it possible to receive the drug by injection once every three months."

Developed by ViiV Healthcare and GlaxoSmithKline, and previously known as GSK744 LA, cabotegravir is an antiretroviral drug. Antiretrovirals interfere with HIV's ability to replicate itself using a host cell and they are used to treat an HIV infection or to prevent those at high risk from acquiring it in the first place.

Cabotegravir belongs to a group of antiretrovirals that target integrase, an enzyme the virus uses to integrate itself into the cell's genome. This compound is a relative of an already FDA-approved integrase inhibitor, dolutegravir, but with chemical properties that allow it to be formulated into a long-acting suspension for injection.

A previous study by the ADARC and Rockefeller team in collaboration with ViiV Healthcare and GSK found long-acting cabotegravir could protect male rhesus macaque monkeys from exposure to a virus related to HIV. Following up on these results, a phase 2 clinical trial is now underway in a group of 120 men at low risk of infection. Before cabotegravir's effectiveness in high risk individuals can be tested, trials must show that study participants tolerate the drug well and find the quarterly injections, which are a novel approach to HIV prevention, acceptable.

Both new animal studies were conducted with women in mind; in 2013 women accounted for 47 percent of new HIV infections worldwide according to the Joint United Nations Programme on HIV and AIDS. Working separately, two teams tested the drug's ability to block vaginal transmission in two species of monkeys with different breeding cycles and susceptibility to infection.

First author Chasity Andrews, a postdoctoral fellow at ADARC and Rockefeller, and colleagues at ADARC, the Tulane Regional Primate Center and ViiV/GSK, studied female rhesus macaques treated with progesterone to increase their susceptibility to the virus. They found injections of long acting cabotegravir were 90 percent effective at protecting the monkeys from repeated high-dose exposures to the virus.

Meanwhile, the complementary study conducted by researchers at the CDC and ViiV/GSK found female pigtail macaques injected with cabotegravir were completely protected against multiple exposures to the virus.

"While we are still a long way off from showing that this drug works for HIV prevention in humans, our hope is that it may one day offer high risk women, as well as men, an additional option for HIV prevention," Markowitz says. "One of the lessons we have learned from contraception is the more options available, the better. We are hoping for the same in HIV prevention -- more options and better results."

Source: Rockefeller University

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How llamas' unusual antibodies might help in the fight against HIV/AIDS

Llamas contribute to the fight against AIDS. Credit: Nika Stropakke, CC-BY

Most vaccines work by inducing an immune response characterized by neutralizing antibodies against the respective pathogen. An effective HIV vaccine has remained elusive so far, but researchers have continued to make progress, often employing innovative methods. A study published on December 18th in PLOS Pathogens reports that a combination of antibodies from llamas can neutralize (destroy) a wide range of circulating HIV viruses.

After initial disappointment that HIV vaccine candidates were unable to elicit neutralizing antibodies, researchers found that some HIV-infected individuals did produce such antibodies. The current challenge is therefore to find safe and effective vaccine formulations (as opposed to HIV infection) that trigger the development of neutralizing antibodies that can recognize and prevent infection with all or most circulating HIV subtypes.

Many known neutralizing antibodies are directed against a specific part of the virus that binds to the CD4 receptor on the human target cells, and structural biology studies indicated that the site is a narrow groove. Antibodies in most mammals are relatively large proteins made up of two copies of two different individual parts (or chains), and bulkiness might be one reason why neutralizing antibodies are rare. Llamas are a notable exception: besides the common four-chain antibodies they also produce smaller ones made up of only two of the four chains. Robin Weiss, an HIV expert, and Theo Verrips, a llama antibody expert, therefore started working with this unconventional research animal.

Laura McCoy (working with Weiss at University College London, UK) led an international group of researchers to test immunization protocols and the resulting immune response in llamas. Having previously identified one particular HIV neutralizing llama antibody, for this study the researchers immunized two additional llamas and identified a total of three new neutralizing antibodies. The four HIV neutralizing llama antibodies target different parts of the CD4-binding site of the virus, and the researchers could show that when used in combination, rather than interfering with each other, they are more potent and can neutralize all of the 60 different HIV strains tested.

To understand how the llama immunization--which included two sets of four sequential vaccine injections per animal--worked, the researchers sequenced many copies of antibody-coding genes from blood cells collected after the first set of immunizations and after a further four rounds of vaccination. They also looked at the "naïve" antibody repertoire from seven llamas that had not been vaccinated. The results suggest that the neutralizing antibodies were not part of the pre-immunization repertoire, nor were they detectable after the first vaccination round. Rather, they were generated as immune cells repeatedly encountered the vaccine and responded by maturing specific antibodies that can recognize it.

While it is encouraging that broadly neutralizing antibodies were found in all of the immunized llamas, they are present only at low concentrations in the blood, and so fail to meet the goal for a protective HIV vaccine. Nonetheless, the researchers conclude that the llama model has allowed them to examine the generation of four broadly neutralizing antibodies induced by vaccination, which has not been possible in any other species.

Source: PLOS.

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New molecules to burst malaria's bubble

Dr Natalie Spillman. Credit: Alex Maier

Scientists have released details of a raft of new chemicals with potent anti-malarial properties which could open the way to new drugs to fight the disease.

A new paper in PNAS is the third published recently by a group at the Australian National University (ANU). The group has collaborated with scientists from around the globe to uncover potential ammunition in the fight against malaria.

Over 200 million people contract malaria each year, and the parasite that causes the disease has become resistant to most of the drugs currently available.

"The series of papers shows that the malaria parasite has a real Achilles heel, and describe a range of new ways to attack it," said Professor Kiaran Kirk, Dean of the College of Medicine, 
Biology and Environment and one of the scientists involved in the project.

Dr Natalie Spillman, from the Research School of Biology at ANU studied the mechanism by which the parasites are killed.

"The new molecules block a molecular salt pump at the surface of the parasite, causing it to fill up with salt," Dr Spillman said

"This has the effect of drawing water into the parasite, causing it to swell uncontrollably and burst."

Although the process of developing the new compounds into clinical drugs is complex and lengthy, Professor Kirk is optimistic the findings will lead to new treatments.

"It's very early days, but these pump-blocking compounds have some of the most promising anti-malarial potential we've seen," he says.

Aspects of the work were carried out with groups at Griffith University, Monash University and the Menzies School of Health Research in Darwin.

"This is a good example of a long-term, international drug development program in which Australian groups have played a key role," he said.

Source: Australian National University

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Drugs in the environment affect plant growth

Lettuce plants (stock image). The potential for some chemicals to influence plants is becoming increasingly relevant, particularly as waste management systems are unable to remove many compounds from our sewage. Drugs for human use make their way into soil through a number of routes, including the use of sewage sludge as fertilizer and waste water for irrigation.
Credit: © riderfoot / Fotolia

By assessing the impacts of a range of non-steroidal anti-inflammatory drugs, the research has shown that the growth of edible crops can be affected by these chemicals -- even at the very low concentrations found in the environment.

Published in the Journal of Ecotoxicology and Environmental Safety, the research focused its analysis on lettuce and radish plants and tested the effects of several commonly prescribed drugs, including diclofenac and ibuprofen. These drugs are among the most common and widely used group of pharmaceuticals, with more than 30 million prescribed across the world every day.

The potential for these chemicals to influence plants is becoming increasingly relevant, particularly as waste management systems are unable to remove many compounds from our sewage. Drugs for human use make their way into soil through a number of routes, including the use of sewage sludge as fertilizer and waste water for irrigation.

This study looked for a number of changes in edible plants, assessing factors such as water content, root and shoot length, overall size and how effectively the plants photosynthesised.

Each drug was shown to affect the plants in very specific ways, with marked differences between drugs that are closely related. For example, drugs from the fenamic acid class affected the growth of radish roots, whilst ibuprofen had a significant influence on the early root development of lettuce plants.

Dr Clare Redshaw, one of the scientists leading the project at the Medical School's European Centre for Environment & Human Health, said: "The huge amounts of pharmaceuticals we use ultimately end up in the environment, yet we know very little about their effects on flora and fauna. As populations age and generic medicines become readily available, pharmaceutical use will rise dramatically and it's essential we take steps towards limiting environmental contamination. We haven't considered the impact on human health in this study, but we need to improve our understanding quickly so that appropriate testing and controls can be put in place."

There have been growing concerns about the presence of pharmaceuticals in the environment, particularly as evidence emerges of the effects they can have on the development of animals and antibiotic resistance in bacteria. Yet their ability to affect plant growth is poorly understood.

This study marks an important step in an emerging research field attempting to assess how very low concentrations of drugs can affect the growth of crucial crop plants. It specifically considered the non-steroidal anti-inflammatory drugs tolfenamic acid, meclofenamic acid, mefenamic acid, diclofenac, naproxen and ibuprofen.

Source: University of Exeter

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