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

New tool for exploring cells in 3D created

The new software can generate editable models of mid-size biological structures such as this one of HIV. Credit: Image created by Graham Johnson and Ludovic Autin of The Scripps Research Institute

Researchers can now explore viruses, bacteria and components of the human body in more detail than ever before with software developed at The Scripps Research Institute (TSRI).

In a study published online ahead of print December 1 by the journal Nature Methods, the researchers demonstrated how the software, called cellPACK, can be used to model viruses such as HIV.

"We hope to ultimately increase scientists' ability to target any disease," said Art Olson, professor and Anderson Research Chair at TSRI who is senior author of the new study.

Putting cellPACK to the Test

The cellPACK software solves a major problem in structural biology. Although scientists have developed techniques to study relatively large structures, such as cells, and very small structures, such as proteins, it has been harder to visualize structures in the medium "mesoscale" range.

With cellPACK, researchers can quickly and efficiently process the data they've collected on smaller structures to assemble models in this mid-size range. Previously, researchers had to create these models by hand, which took weeks or months compared with just hours in cellPACK.

As a demonstration of the software's power, the authors of the new study created a model of HIV showing how outer "spike" proteins are distributed on the surface of the immature virus.

The new model put to the test a conclusion made by HIV researchers from super-resolution microscopic studies -- that the distribution of the spike proteins on the surface of the immature virus is random. But by using cellPACK to generate thousands of models, testing alternative hypotheses, the researchers found that the distribution was not random. "We demonstrated that their interpretation of the distribution did not match that hypothesis," said Olson.

A Team Effort

The cellPACK software began as the thesis project of a TSRI graduate student, Graham Johnson, now a QB3 faculty fellow at the University of California, San Francisco (UCSF) who continues to contribute to the project. Johnson had more 15 years' experience as a medical illustrator, and he wanted to create an easy way to visualize mesoscale structures. cellPACK is an expansion of Johnson's autoPACK software, which maps out the density of materials -- from concrete in a building to red blood cells in an artery.

The researchers see cellPACK as a community effort, and they have made the autoPACK and cellPACK software free and open source. Thousands of people have already downloaded the software from http://www.autopack.org.

"With the creation of cellPACK, Dr. Olson and his colleagues have addressed the challenge of integrating biological data from different sources and across multiple scales into virtual models that can simulate biologically relevant molecular interactions within a cell," said Veersamy Ravichandran, PhD, of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. "This user-friendly tool provides a new platform for data analysis and simulation in a collaborative manner between laboratories."

As new information comes in from the scientific community, researchers will tweak the software so it can model new shapes. "Making it open source makes it more powerful," said Olson. "The software right now is usable and very useful, but it's really a tool for the future."

Source: Scripps Research Institute

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.