Almost everyone is familiar with HIV, but far fewer have heard about HTLV-1, its less-known counterpart. HTLV-1 can lead to serious health issues, including cancer. To find ways to fight against this virus, it is crucial to understand its structure.
While many people recognize HIV, the related virus HTLV-1 often gets less attention. Nonetheless, HTLV-1 poses significant health risks, including cancer. Gaining insight into its structure is vital for developing methods to tackle this virus. Martin Obr and Florian Schur from the Institute of Science and Technology Austria (ISTA), along with their colleagues in the U.S., have provided an in-depth look at the virus in a new study published in Nature Structural & Molecular Biology.
Martin Obr is filled with anticipation as he waits for his train to the airport during an impending storm named “Sabine,” which has caused disruptions in public transport. He narrowly catches his flight from Frankfurt to Vienna.
In the preceding days, Obr was busy in Germany conducting a detailed analysis of what he describes as the “perfect sample,” which was instrumental in helping him and Florian Schur at ISTA to decode the structure of HTLV-1 (Human T-cell Leukemia Virus Type 1).
Through collaboration with the University of Minnesota and Cornell University, the researchers have unveiled fresh insights into the virus’s architecture with the help of Cryo-Electron Tomography (Cryo-ET)—a technique that enables the study of biomolecule structures in high resolution. Their findings were published in Nature Structural & Molecular Biology.
A Relative of HIV
Obr and Schur first met while researching HIV-1 (Human Immunodeficiency Virus Type 1) to enhance the understanding of its structure. Eventually, Obr joined Schur’s research team at ISTA as a postdoctoral researcher, where they shifted their focus to HTLV-1, a lesser-known virus belonging to the same retrovirus family as HIV-1, due to the limited understanding of its structure. “HTLV-1 is somewhat the overlooked cousin of HIV,” Schur remarks. “While it is less common than HIV-1, many individuals are affected globally.”
The World Health Organization estimates that between 5 and 10 million people are currently infected with HTLV-1. While the majority of cases remain without symptoms, approximately 5% can escalate into severe diseases such as adult T-cell leukemia/lymphoma, a type of cancer with a poor prognosis.
“HTLV-1, as a significant human pathogen that can cause serious diseases, should be at the forefront of our research efforts to better understand its functions and structure,” Obr emphasizes.
The Virus Structure
The researchers focused on the structure of the virus particle, which had previously been poorly understood. “When a virus is produced, it forms a particle that is not yet infectious. This immature virus particle must mature to become infectious,” Schur explains. The structure of the HTLV-1 particle is formed by a protein lattice that creates a spherical shell. This shell serves a vital role by safeguarding the viral genetic material until it can infect a host cell. But what exactly does this lattice look like, what are its main components, and how does it compare to other viruses? “We anticipated some differences relative to other viruses, but the extent of the differences astonished us,” Obr shares.
A Distinct Virus
The analysis indicated that the immature HTLV-1 lattice is significantly different from those of other retroviruses. Its building blocks are arranged in a specific manner that distinguishes its overall architecture. Additionally, the ‘glue’ that holds it together is also unique. In most retroviruses, the lattice comprises a top and bottom layer, with the bottom layer providing structural stability and the upper layer defining the shape. “For HTLV-1, it’s the opposite. The bottom layer is virtually just hanging on,” notes Schur. This leads to questions about why HTLV-1 possesses such a different lattice structure. A possible reason could be its unique method of transmission. HTLV-1 spreads through direct contact between an infected cell and an uninfected cell, while HIV-1 can move through the bloodstream without needing direct contact. “From an evolutionary perspective, altering its lattice structure may have been advantageous for HTLV-1 in terms of transmission. However, this remains speculation until we can confirm it through experiments,” Obr adds.
Potential New Treatment Options
Understanding these structural characteristics is an important step, as the findings may lead to novel treatment strategies against HTLV-1 infections. Researchers can explore different ways to disrupt retrovirus infectivity. For instance, one could block the mature virus during the infection stage or target the immature virus to stop it from developing into an infectious form. With this study detailing the structure of the immature virus, researchers are now positioned to devise approaches to address the virus during its maturation process.
“There are various types of viral inhibitors that can interfere with the assembly of the virus by targeting its building blocks to prevent their combination. Others might destabilize the lattice structure,” Schur explains. “The possibilities are extensive.”
The Ideal ‘Ice Cold’ Sample
Despite their background in studying similar viruses like HIV-1, this research on HTLV-1 presented its unique challenges. Obr’s “perfect sample” was a breakthrough in their research.
For safety reasons, this sample does not contain the actual virus; instead, researchers created virus-like particles in mammalian cell cultures or produced viral components in bacterial cultures. “When these components are put in suitable conditions, they self-assemble into structures resembling the actual immature virus,” Schur clarifies. These non-infectious particles are quickly frozen and preserved at -196 °C in liquid nitrogen, and then viewed using a Cryo-Electron Microscope (Cryo-EM), which captures high-resolution images down to a nanometer scale.
But can scientists trust that they’re observing the real structure?
A valid concern, as Obr assesses, “Our virus-like particles are only missing a few enzymes necessary for maturation. There’s no reason to believe that the actual immature particles appear significantly different.” This meticulous approach allows researchers to safely study the virus while gaining crucial knowledge.
