Test Scientists Map 3D Structure of Ancient Viral Proteins in Human DNA

A groundbreaking study has successfully mapped the three-dimensional structure of HERV-K proteins, remnants of ancient viruses integrated into human DNA. This significant achievement, led by researchers at the La Jolla Institute for Immunology (LJI), utilized cryo-electron microscopy to visualize these elusive proteins. The findings reveal a unique protein conformation and herald a new era for diagnosing and treating a range of diseases, including cancer and autoimmune disorders, where these ancient viral fragments are implicated.

Human DNA harbors approximately 8% of genetic material derived from ancient viruses that integrated over millions of years of evolution. These viral fragments, often referred to as "genomic dark matter," are typically dormant but can reactivate in certain disease states. The HERV-K proteins, in particular, have presented a challenge to researchers due to their inherent instability. However, the team at LJI, under the leadership of Erica Ollmann Saphire, has overcome this hurdle.

By employing cryo-electron microscopy, they were able to capture detailed images of these proteins across three stages of their lifecycle, effectively stabilizing them without altering their natural form. This method allowed for an unprecedented look at HERV-K. The research, published in Science Advances, unveiled a distinct, tall, and slender conformation for HERV-K proteins, setting them apart from other retroviral proteins like those found in HIV and SIV. This unique structure may shed light on their peculiar evolutionary journey alongside the human species.

Furthermore, the team successfully developed specific antibodies capable of recognizing these HERV-K proteins. These antibodies demonstrated a remarkable ability to differentiate between healthy individuals and those suffering from conditions such as rheumatoid arthritis and lupus. They also accurately identified HERV-K proteins on the surface of cancer cells in breast and ovarian carcinomas. Jeremy Shek, a postdoctoral fellow at LJI and a co-first author of the study, highlighted the potential of these discoveries.

"In many disease states, like autoimmune diseases and cancer, these genes re-awaken and start making pieces of these viruses," Saphire stated. "Understanding the HERV-K Env structure, and the antibodies we now have, opens up diagnostic and treatment opportunities." The ability to target HERV-K proteins on cancer cells offers a promising avenue for developing highly specific immunotherapies, potentially minimizing harm to healthy tissues. Similarly, their presence in autoimmune diseases suggests they could serve as valuable diagnostic biomarkers.

This research not only deepens our understanding of the intricate interplay between human genetics and ancient viral elements but also offers tangible pathways for medical innovation. The ability to visualize and characterize the HERV-K protein structure represents a significant technical achievement, overcoming previous limitations and paving the way for novel diagnostic tools and therapeutic strategies for complex diseases that affect millions worldwide. The findings underscore the enduring influence of evolutionary processes on contemporary health and disease, emphasizing the importance of exploring the vast, often-overlooked, regions of our genome.