Transmission electron micrograph of AIDS, HIV-1
Transmission electron micrograph of AIDS, HIV. [Callista Images/Getty Images]

A new study led by researchers at The Wistar Institute, and published in the journal Nature Communications, reports the development of a unique native-like trimer (NLT) conformation of the HIV envelope that can generate neutralizing antibodies against difficult to neutralize HIV (tier-2) strains in mice. The study is a promising step toward developing an HIV vaccine.

“We have enabled direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology in the vaccinated animal,” said David Weiner, PhD, executive vice president and director of the Vaccine & Immunotherapy Center, professor at The Wistar Institute and a co-author of the study.

“Our data, demonstrating induction of autologous tier-2 neutralization illustrate the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV,” said Weiner.

The authors encoded the HIV NLT into DNA. DNA vaccines involve engineering and administering DNA in a host for in vivo production of an antigen to elicit immune responses. While DNA vaccines showed sub-optimal efficacy in early studies in large animals and humans, technological advances in antigen design, nucleic acid formulations, genetic adjuvants, and adaptive electroporation have led to more potent and consistent responses in several clinical studies on Zika, MERS and Ebola.

“Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines,” the authors note.

In addition, experiments toward vaccine development using rabbits and macaques—animal models used in earlier HIV studies—are costly and lack throughput, posing a significant bottleneck. “With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce tier-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, PhD, associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author on the paper.

Immunizing mice with NLTs have generally failed to induce tier-2 neutralizing antibodies. But in the current study, the investigators have succeeded in developing DNA-encoded NLTs that fold properly and induce autologous tier-2 neutralizing antibodies in mice. The DNA-encoded NLTs also uniquely induce both CD4 and CD8 classes of T-cells compared to protein immunizations.

The researchers compared the immunization results from mice that received the DNA-encoded NLT to results from mice who received a standard protein immunization. Only mice that received the DNA-encoded NLT developed tier-2 neutralizing antibodies. “We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” said Kulp.

Kulp and his colleagues isolated monoclonal antibodies from mice immunized using the DNA-encoded NLT. Using advanced sequencing technology they identified neutralizing antibodies in mice and using cryo-electron microscopy (cryoEM) they determined the atomic structure of a tier-2 neutralizing monoclonal antibody bound to the viral envelope.

Antibodies that bind to the specific site (C3/V5 epitope) on the viral envelope revealed by the cryoEM interaction analysis in the current study, have been shown to protect animals from related infections such as SHIV in earlier studies.

“The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp. “For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope.”

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