Preclinical Study Offers Hope for New Approach to Controlling HIV

A team of scientists from The Scripps Research Institute (TSRI) and other institutions demonstrated that a group of recently discovered monoclonal antibodies could be a new tool that can control HIV.

The new study, published online ahead of print on October 30, 2013 by the journal Nature, showed the antibodies typically stay active for several weeks in rhesus monkeys affected by an HIV-like virus, the simian-human immunodeficiency virus (SHIV), limiting the virus to low levels.

“The antibodies brought down the virus very quickly and dramatically and it stayed there, in most cases, until the antibodies went away. In some cases, the virus stayed undetectable,” said Dennis Burton, professor and director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI and the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and member of the Steering Committee of the Ragon Institute. “It's surprising and encouraging that antibodies can be so effective against established infection.”

The study—which was led by Dan H. Barouch of Beth Israel Deaconess Medical Center and the Ragon Institute, jointly with Burton and Michel C. Nussenzweig of The Rockefeller University and Howard Hughes Medical Institute—breaks new ground, especially as previous research in mouse models had found only a short-lived effect from single antibodies, with the virus rebounding quickly. It should be pointed out that the mouse model doesn’t have its own immune system, but the monkey does and it’s a much closer to human infection.

The promising results open up possibilities for using antibodies in combination with antiretroviral drugs now used to treat HIV. These drugs tackle the replicating virus, whereas antibodies target the free virus as well as the virally infected cell. Combining current antiretroviral drugs, which are limited by resistance and toxicity, with monoclonal antibodies could lead to more effective treatment regimes and possibly contribute to HIV cure strategies. 

One Powerhouse

Antibodies are proteins produced by the immune system in response to foreign “invaders,” such as viruses and bacteria. Monoclonal antibodies (clones of a unique parent or ancestral cell) can be used therapeutically by stimulating the patient’s immune system to attack certain cells. Dozens of drugs on the market are based on monoclonal antibody technology, including therapies for rheumatoid arthritis, multiple sclerosis, breast cancer and lupus, among other conditions.

In a previous study in Nature (477: 466–470 (September 22, 2011)) led by Burton and his colleagues at TSRI and IAVI, the researchers had described a number of antibodies that broadly neutralized HIV. One of these was called PGT121.

At the beginning of the new study, the scientists thought they would need a cocktail of antibodies to suppress the virus, so they started with three, which worked well. They then experimented with only two, which also worked; so they tried it with just PGT121, which also proved to be effective. “Everything we’ve seen could have been because of that one antibody,” Burton said.

Going forward, the researchers plan to gain a better understanding of why PGT121 is effective against the virus, as well as exploring the effect of combining antibodies with existing drugs.

“We hope we learn the right lessons from this so we can do the right kind of clinical trials in humans,” Burton said. “That will be the next big step, probably in one or two years.”

In addition to Burton, Barouch and Nussenzweig, authors of the study, “Therapeutic efficacy of potent neutralizing HIV – 1 – specific monoclonal antibodies in SHIV-infected rhesus monkeys” were: James B. Whitney Jinyan Liu, Kathryn E. Stephenson, Hui-Wen Chang, Joseph P. Nkolola, Michael S. Seaman, Kaitlin M. Smith, Erica N. Borducchi, Crystal Cabral, Jeffrey Y. Smith, Stephen Blackmore, Srisowmya Sanisetty and James R. Perry of Beth Israel Deaconess Medical Center, Harvard Medical School; Brian Moldt and Pascal Poignard of TSRI; Florian Klein and Thiago Y. Oliveira of The Rockefeller University; Karthik Shekhar and Sanjana Gupta of Massachusetts Institute of Technology (MIT); Matthew Beck of New England Primate Research Center; Mark G. Lewis of Bioqual, Inc.; William Rinaldi of Alpha Genesis, Inc.; Arup K. Chakraborty of Ragon Institute of MGH, MIT, and Harvard and MIT.

The research was funded by grants from the National Institutes of Health (AI055332; AI060364; AI078526; AI084794; AI095985; AI096040; AI10063; AI100148, AI100663), the Bill and Melinda Gates Foundation, the Ragon Institute of MGH, MIT, and Harvard, the Lundbeck Foundation and the Stavros Niarchos Foundation.

For more information on the paper, see http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature12744.html

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