by Researchers have made significant advancements in understanding the complex structures and behavior of the human immunodeficiency virus (HIV) proteins. HIV is a highly mutating pathogen with structures that protect it from recognition and attack by antibodies and therapeutics, making it challenging to treat. By studying the envelope protein of HIV, which plays a crucial role in the virus’s infection process, researchers hope to develop new therapeutics and vaccines.
The envelope protein of HIV is trimeric, resembling a flower with three stem portions (gp41) and three petal regions (gp120). When the virus prepares to infect a T cell, the envelope protein undergoes shape-shifting changes. The gp120 proteins bind to the CD4 receptor on the T cell, exposing sites that are recognized by a host co-receptor. Subsequently, a needle-like structure emerges, enabling the virus to find entry into the cell.
Researchers sought to understand what happens when only one or two CD4 receptors are bound by the gp120 petals. Can the envelope protein fully open up to facilitate infection? This knowledge is crucial for developing targeted therapeutics. To answer this question, the team developed a protocol to create stable heterotrimers, which are envelope proteins that bind only one or two CD4 receptors. Cryo-electron microscopy was used to capture images of the heterotrimers’ structures bound to CD4 receptors.
The imaging revealed that when only one or two CD4 receptors are bound, the envelope protein cannot fully open up and undergo the shape-shifting process necessary for infection. This discovery raises the question of whether envelope proteins that do not fully open up can still facilitate infection.
The research team collaborated with Yale University to compare their findings with similar attempts to image heterotrimers. The results showed that the behavior of engineered heterotrimers in a test tube closely resembles the behavior of envelope proteins on the viral surface during an infection. This finding is significant as soluble constructs in test tubes are commonly used in developing new therapeutics, and understanding their accuracy in mimicking natural processes is crucial.
The breakthrough in imaging and structural biology research not only enhances our understanding of HIV but also provides insights into other viruses. Lessons learned from HIV have been applied to research on SARS-CoV-2 during the COVID-19 pandemic.
The previously unknown intermediate envelope conformations offer valuable insights into the structural changes driven by receptor interactions before host and viral membrane fusion. This research opens new avenues for studying the complexities of HIV infection and enhances our understanding of viral dynamics, extending beyond therapeutic design.
