May 4, 2016

April's featured paper is "Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques," published in Nature Medicine. The paper is published by a team led by Drs. Nancy Haigwood and Ann Hessell.

Human mothers who are HIV-positive transmit the virus to their children primarily during childbirth and, to a lesser extent, through breastfeeding.

To prevent transmission, a combination of measures is given to mothers and infants, including antiretroviral therapy (ART), Cesarean-section delivery and formula feeding, rather than breastfeeding. As a result, the rate of mother-to-child HIV transmission has decreased from 25 percent to less than two percent since 1994.

Despite this decrease, approximately 300,000 newborns worldwide continue to become infected with HIV each year, primarily in developing countries where access to ART may be limited.

Even with this treatment strategy, risks remain, including toxicities associated with long-term ART use, the development of drug-resistant viral variants and lack of access to prenatal care prior to delivery.

Could a better intervention strategy be developed to prevent infection at birth? One with less toxicity and which would quickly eliminate all sites of infection throughout the body?

Powerful antibodies

Recent findings by a team of OHSU scientists led by Nancy Haigwood, Ph.D., director and senior scientist and the Oregon National Primate Research Center at OHSU, and Ann Hessell, Ph.D., ONPRC assistant scientist, published in Nature Medicine suggest an answer: Powerful antibodies given at birth.

Mary Heinricher, Ph.D., associate dean for basic research in the OHSU School of Medicine, selected the study as the school's Paper of the Month. "The potential these antibodies could have in treating babies of HIV-positive mothers is intriguing," said Dr. Heinricher. "This honor is well deserved."

In adult macaque-animal studies, the Haigwood lab and other groups have shown that antibodies capable of neutralizing HIV can prevent an infection when the antibodies are already present at the time of exposure to virus. 

"These protection studies model human transmission events using similar routes of exposure," said Dr. Haigwood. "They use a special chimeric virus, SHIV, that is specifically designed to interact with human HIV-antibodies and that models AIDS in non-human primates."

Recently, several new and much more powerful human monoclonal antibodies have been discovered that are practical for testing in humans.

Modeling infection at birth

Unlike protection studies that show antibodies can be protective if given before a virus exposure, the lab decided to test them after exposure, a higher-risk situation to model infection at birth. 

Although scientists know that HIV infection begins within hours after an exposure, it is not known how long it takes before the virus spreads widely into tissues and organs, setting up permanent infection sites. 

The lab was able to demonstrate that infection occurred throughout most lymph and gut areas and also some organs within 24 hours after contact with the virus.

"Because so much virus had spread into a wide range of tissues and locations, we knew it was replicating above and beyond the initial dosage," said Dr. Haigwood. Thus, when researchers started the antibody treatment at 24 hours, the virus had already taken foothold.

Remarkably, the team found that the antibodies not only quickly disseminated to diverse sites in the body and stopped the infection, but also cleared out all of the virus.

"This means that we revealed a new concept of how certain powerful antibodies against HIV can work to recognize and remove infected cells at least in early stages of infection," said Dr. Haigwood. "This type of function is not uncommon for antibodies that fight other diseases, but it has not been shown for HIV.

Over the course of the study, researchers administered the antibody treatment for at least two weeks to maintain high levels of antibodies. The results were complete eradication of SHIV from the monkeys by 14 days. No signs were found six months later, even when the team tried to restart the infection by hindering part of the immune system.

Next steps

The antibody doses required to prevent infection in monkeys are low enough that it is now reasonable to use HIV antibodies as part of therapy to accompany ART, concluded the team.

The researchers' next step will be to define the window of time for the antibody intervention to insure that virus infection can be eradicated. It will also test other variables including antibody dose, other combinations of antibodies, and how long dosing is needed. The lab also hopes to expand the model to juvenile and adult monkeys. 

"Our collaborators at NIH are starting clinical testing one of the antibodies for pre-exposure prophylaxis (PrEP) in adults," said Dr. Haigwood. "They are also working with the IMPAACT network to test human HIV antibodies in the clinic in newborns, and this network has expressed strong interest in our work."

In addition, even more powerful antibodies against HIV are still being discovered, thanks to new technologies. Modifications of these antibodies can be engineered to result in more potent, longer-lasting and non-toxic treatments for patients. Eventually, new formulations and methods of delivery may lead to easy and cost-effective production methods for global distribution.

"In the absence of a preventive HIV vaccine, the results of cure research strategies such as ours in this model could potentially change the outcome for those who face life-long infection and treatments with ART," said Dr. Haigwood.

Resources

• Read the paper
• Read the media release
• Read about the Haigwood lab

Citation

Hessell, A. J., et al. (2016). "Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques." Nat Med Mar 21. doi:10.1038/nm.4063

More Published Papers

• Previous School of Medicine Papers of the Month
• Recent OHSU published papers

Pictured above, from left to right: Philip Barnette, Nancy Haigwood, Jonah Sacha, Bill Sutton, Ann Hessell, Shilpi Pandey, Tracy Cheever.