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Wistar Science Highlights: Advancements in HIV and New Applications of Synthetic DNA Technology for Ebola and High Cholesterol

In a study published recently in JAIDS, the lab of Luis J. Montaner, D.V.M., D.Phil., director of the HIV-1 Immunopathogenesis Unit in Wistar’s Vaccine & Immunotherapy Center and the Herbert Kean, M.D., Family Endowed Chair Professor, shed light on the mechanisms of resistance to HIV infection.

A small percentage of individuals who are at high risk of HIV infection because of their continued exposure to the virus remain uninfected. Previous research from the Montaner Lab has shown that these individuals, referred to as HIV-1 exposed seronegative (HESN), have a higher level of activation of immune cells called natural killer (NK) cells and dendritic cells that play a key role in the host immune defense during the earliest phases of viral infection.

This new study focused on people who inject drugs (PWID) and are at high risk of HIV infection because of needle sharing but don’t become infected — referred to as HESN-PWID. Montaner and colleagues found that these individuals have a significantly higher expression of the S100A14 protein in their blood and within their NK cells compared with control donors. 

They also showed that S100A14 potently activates a population of immune cells in the blood called monocytes, which in turn activate NK cells. These findings suggest that S100A14 represents a novel element in the host defense against HIV infection.

“Understanding the basis of natural resistance to HIV is important because it may instruct us on how to manipulate the host immune system to prevent HIV infection,” said Montaner.

David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, and collaborators demonstrated two innovative applications for synthetic DNA-encoded monoclonal antibody (DMAb) technology. 

In one study, published online in Cell Reports, they successfully engineered novel DMAbs targeting Zaire Ebolavirus that were effective in preclinical models. 

Ebola virus infection causes a devastating disease for which no licensed vaccine or treatment are available. A new outbreak is ongoing in the Democratic Republic of Congo, with a death toll of more than 200 people since August. One of the experimental avenues scientists are pursuing is evaluating the safety and efficacy of monoclonal antibodies isolated from survivors as promising candidates for further development as therapeutics against Ebola virus infection. However, this approach requires high doses and repeated administration of recombinant monoclonal antibodies that are complex and expensive to manufacture. 

The team designed and enhanced optimized DMAbs that, when injected locally, provide the genetic blueprint for the body to make functional and protective Ebola virus-specific antibodies, circumventing multiple steps in the antibody development and manufacturing process. Dozens of DMAbs were tested in mice and the best-performing ones were selected for further studies. These proved to be highly effective for providing complete protection from disease in challenge studies.

“The DMAb platform allows us to collect protective antibodies from protected persons and engineer them rapidly and then deliver them in vivo to protect against infectious challenge. Such an approach could be important during an outbreak, when we need to design, evaluate and deliver life-saving therapeutics in a time-sensitive manner,” said Weiner.

The researchers also showed that in vivo expression of DMAbs supports extended protection over traditional antibody approaches.

The second study by the Weiner Lab, published online in Molecular Therapy, demonstrated the first use of the DMAb approach for chronic disease therapy. Weiner and colleagues developed a novel experimental lipid-lowering therapeutic strategy based on DMAbs directed against PCSK9, a protein involved in regulating cholesterol levels in the bloodstream.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease, the leading cause of death in the nation and worldwide. Statins are effective and widely used cholesterol-lowering medications, but have been associated with a number of side effects that have prompted development of alternative treatment strategies, including monoclonal antibodies targeting the PSCK9 protein.

The team engineered synthetic DNA constructs that are delivered locally and encode the genetic instructions for the body to make its own anti- PSCK9 monoclonal antibodies, entirely bypassing bioprocess and manufacturing factory approaches. This study provides a proof of principle that such engineered DMAbs may be developed as a new option for coronary artery disease.     

A single intramuscular administration in mice drove robust antibody expression within days and for up to two months resulting in a significant cholesterol decrease.