Delivering broadly neutralizing antibodies against HIV-1 to newborns via gene therapy provided them with multi-year protection from HIV/AIDS infection, according to an animal study led by scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.
With further research, the strategy could offer a relatively simple way to prevent transmission of HIV-1 during breastfeeding in parts of the world with limited medical resources, said lead author Mauricio Martins, Ph.D., associate professor in the department of immunology and microbiology at The Wertheim UF Scripps Institute.
The advent of antiretroviral drugs has dramatically lowered the risk of mother-to-child HIV transmission in developed countries. However, globally, hundreds of thousands of children continue to contract HIV-1 each year, mostly in sub-Saharan Africa. One reason is due to mothers’ difficulties obtaining the needed antiretroviral medications, especially during the breastfeeding period, Martins said.
“In sub-Saharan Africa, you have mothers living with HIV tasked with taking their own medicines, and also administering drugs to their babies, sometimes multiple times a day,” Martins said. “This is an intervention that you would give one time at birth, and they would not need it again for years.”
In the study published July 30 in the journal Nature, the scientists reported administering the gene therapy once to primates of different ages through simple injections into muscle tissue. The shots consisted of a common gene therapy shuttle, called adeno-associated virus, containing the genetic instructions for cells in the body to produce an HIV-1-specific, broadly neutralizing antibody called 3BNC117. A broadly neutralizing antibody is one able to neutralize a wide variety of HIV strains. The 3BNC117 antibody was discovered in 2011 by a group led by Michel Nussenzweig, M.D., Ph.D., at The Rockefeller University.
Martins’s study showed that while the shot resulted in robust production of the protective antibody in nearly 90% of newborn macaques, the success rate of the intervention decreased when it was administered to older infants. Nearly all dosed at birth were protected from infection with simian-HIV in an oral challenge model that simulated HIV-1 transmission through breastfeeding. There were no side effects documented, Martins said, and the protection afforded by the shot lasted for several years, even as the animals reached adolescence.
One benefit of the strategy is that the viral gene therapy system is very stable, so it could be used in remote settings where ultra-cold chains cannot be reliably maintained, he said.
The researchers also found that exposure to the broadly neutralizing antibody during pregnancy provided benefits to offspring. The offspring did not develop the immune defense reaction that caused treatment failure in other young animals.
The next step will be to conduct clinical trials in humans. Martins said he is hopeful that foundations or non-governmental organizations will step in to continue the work, given its potential for preventing HIV-1 infection.
“The world is changing, underscoring the importance of prioritizing HIV interventions that don’t rely on repeated dosing,” Martins said. “This intervention, given one time and possibly never again, could provide protection to a very vulnerable population.”
The study, “Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life,” appears July 30 in the journal Nature. In addition to Martins, authors from The Wertheim UF Scripps Institute include Daniel O’Hagan, Siddhartha Shandilya, Patricia Hahn and Lucas da Costa. The first author is Amir Ardeshir, currently based at the Tulane National Primate Research Center. Other co-authors include Isha Mehta and Jishnu Das at the University of Pittsburgh; Lincoln Hopkins, Lourdes Adamson, Marcelo Kuroda and Koen Van Rompay of the California National Primate Research Center at the University of California, Davis; Sebastian Fuchs, Jose Martinez-Navio and Ronald Desrosiers of the University of Miami; Matthew Gardner of Emory University; Diogo Magnani of UMass Chan Medical School Nonhuman Primate Reagent Resource; Jeffrey Lifson of the Frederick National Laboratory for Cancer Research; Guangping Gao of UMass Chan Medical School, and Michael Farzan of Harvard Medical School, Boston Children’s Hospital Department of Pediatrics.
This work was supported in part by a National Institutes of Health supplement grant issued to the Miami Center for AIDS Research (P30AI073961); by the Bill and Melinda Gates Foundation, investment OPP1196704 (M.A.M.); and by Public Health Service grants R01HD102252 (M.A.M.) and R01HD103494 (M.A.M.) from the National Institute of Child Health and Human Development.
Additional support came from PHS grants U19AI149646 (M.F.), R01AI175007 (M.A.M.) and U24AI126683 (D.M.M.) from the National Institute of Allergy and Infectious Diseases. Additional support was provided from the National Cancer Institute, NIH, under contract 75N91019D00024/HHSN261201500003I, and from the Office of Research Infrastructure Program, Office of the Director, NIH, through awards P51OD011107 to the California National Primate Research Center and P51OD011104 (RRID: SCR_008167) to the Tulane National Primate Research Center.
M.A.M., M.R.G. and M.F. have financial interests in Emmune Inc., a company that is developing HIV immunotherapies. The other authors declare no competing interests.