Antibody Combination Puts HIV on the Ropes

Source: Rockefeller University, Newswire
Date: 01/25/17
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Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body’s ability to control it. But a small group of infected individuals—called elite controllers—possess immune systems capable of defeating the virus. They accomplish this by manufacturing broadly neutralizing antibodies, which can take down multiple forms of HIV.

Now a study using antibodies from one of these elite controllers has shown that a combination of three such antibodies can completely suppress the virus in HIV-infected mice. The findings, from the laboratory of Michel C. Nussenzweig, who is Zanvil A. Cohn and Ralph M. Steinman Professor at The Rockefeller University and head of the Laboratory of Molecular Immunology, are being reported in Science Translational Medicine.

“Some people with HIV produce these antibodies, but most of the time the virus eventually escapes them through mutations in the antibody’s corresponding epitope,” says postdoctoral fellow Natalia Freund, the study’s first author. The epitope is the part of the virus that antibodies recognize and attach themselves to, and this ability to mutate makes HIV particularly tricky to tame. It ensures that once the virus is in their bodies, people remain infected forever, and this may be the biggest roadblock in developing immune therapies to overcome the virus.

Tug of war

“Think of the relationship between the antibodies and the virus as an arms race that goes on and on,” Freund says. “By mutating, some of the virus may escape the antibodies and continue growing. Years later, the body may produce new broadly neutralizing antibodies against the escaped virus, which in turn may mutate and escape yet again.”

“What we’ve shown in this study is that after several rounds of escape from these particular antibodies, the virus seems to run out of options,” she adds. “In this particular case, HIV eventually loses this arms race.”

An elite controller’s immune system can defeat the virus by coming up with new broadly neutralizing antibodies, and also by producing cytotoxic T cells—immune cells that can recognize and destroy infected cells to immobilize the virus. The patient whose HIV response created antibodies for the study has been working with the Rockefeller team for 10 years, contributing his blood serum for their research. He was infected at least three decades ago, and has developed three different types of broadly neutralizing antibodies that bind to three different sites on the virus.

The remarkable thing about his antibodies is that they seem to complement one another’s activity, completely shutting down HIV.

The investigators gave the three antibodies, called BG18, NC37, and BG1, to HIV-infected mice whose immune systems had been modified to more closely resemble those of humans. They found that the trio rendered the virus undetectable in two-thirds of the mice three weeks after it was administered.

“This study validates the approach of using three different antibodies to control HIV infection,” Freund concludes, “pointing the way toward a potential new treatment for people infected with HIV.”

Atomic-scale view of bacterial proteins offers path to new tuberculosis drugs

Source: Rockefeller University, Newswire
Date: 02/03/17
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With the first detailed analysis of a cellular component from a close relative of the pathogen that causes tuberculosis, Rockefeller scientists are suggesting strategies for new drugs to curb this growing health problem. Each year, nearly half a million people around the world are infected with mutant TB strains capable of evading existing antibiotics.

The research, conducted by a Rockefeller team led by Elizabeth Campbell, in collaboration with scientists at Memorial Sloan Kettering, focuses on a cluster of interacting proteins called RNA polymerase. Crucial to all cells, this protein machine carries out a fundamental process in which genes within the DNA blueprint are copied into RNA. The RNA polymerase is the target of the antibiotic rifampicin—a lynchpin of modern TB treatment, which relies on a combination of drugs. Some bacteria become resistant to rifampicin by acquiring RNA polymerase mutations.

“Now that we can visualize the molecular machinery of the bacteria that the drug targets, we can use a structure-guided approach to better understand how the drug works, how bacteria become resistant to it, and how to potentially improve the drug’s action,” says Campbell, a senior research associate in Seth A. Darst’s Laboratory of Molecular Biophysics. She is one of the senior authors of a report published in the online journal eLife.

A molecular map

To visualize the structure the researchers used an imaging method known as x-ray crystallography. By crystallizing enzymes and other molecules interacting with each other—essentially freezing them in action—investigators are able to see how they fit together, much like keys fitting into locks. This ability to visualize what’s going on can point the way toward more effective drugs, which may be able to latch more securely onto enzymes and other molecules.

“Based on the findings reported in this study,” Campbell says, “we’re already investigating new compounds with new mechanisms of action that appear to inhibit the rifampicin-resistant version of TB. Our eventual goal is to get them into clinical trials investigating new treatments for TB, including rifampicin-resistant TB.”

Rockefeller chemist Sean F. Brady, who was not directly involved in the study, provided the team with these new compounds. He is now working together with Campbell, Darst, and other colleagues to further develop them into antibiotics and characterize the basis of their activity.

Not all bacteria are alike

It’s estimated that up to one-third of the world’s population is infected with M. tuberculosis, the bacterium that causes TB. In the study, the researchers worked with a closely related strain called M. smegmatis. “We needed hundreds of liters of cells to get enough of the material to do the crystallization,” says Elizabeth Hubin, a former Rockefeller graduate student who carried out much of the work. “M. tuberculosis grows too slowly to be able to collect the volume that’s needed, and it’s very dangerous to work with in the lab.”

But M. smegmatis relies on an RNA polymerase that is almost identical in sequence, structure, and behavior to the M. tuberculosis RNA polymerase, which led to another important finding in the study: The RNA polymerase from Escherichia coli, the bacterium most commonly used in lab research, is not. This means there may be a drawback to relying on E. coli as a model when developing certain types of antibiotics for bacteria that cause TB or other diseases.

“Most of the studies previously done with RNA polymerase were done using E. coli,” Campbell says. “We’ve always assumed that the enzyme works the same way in all bacteria, but our study shows we can’t assume what’s found in one bacteria applies to all bacteria.

“Every pathogen needs to be studied individually,” she adds, “so the field has a lot of work to do.”