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Researchers at the University of Michigan have revealed new insights into the method used by HIV to commandeer the transport systems of cells to ensure its own survival.

This study not only challenges a long-standing hypothesis but also presents a novel framework for probing specific elements of viruses outside the cellular context, enhancing understanding of infection mechanisms and potentially identifying new drug targets.

The interiors of cells are not static realms. Specialized subunits within the cell are constantly moving to execute tasks that maintain cell functionality. This intracellular transport occurs on motor proteins that operate like delivery vehicles, carrying cargo along microtubules, which serve as the highways of the cell.

HIV, or human immunodeficiency virus, exploits this transport system to reach its intended locations within host cells. By attaching to the delivery vehicles known as dynein, the virus secures a ride from the cell’s outer regions toward the nucleus, where it integrates its genetic material into the host cell’s genome for replication.

Since the early 2000s, scientists have believed that HIV can board dynein only through the assistance of a cargo adaptor protein, which functions like a trailer hitch connecting the virus and the motor protein. Subsequent studies indicated that a specific adaptor protein named BicD2 was essential for linking HIV to dynein.

A recent investigation from the U-M Life Sciences Institute, published in Science Advances, has overturned that assumption, demonstrating that the virus exhibits greater flexibility in its selection of travel partners.

A research group from the lab of biochemist Michael Cianfrocco at the LSI developed a methodology to investigate HIV trafficking outside of the cellular framework. They isolated dynein motor proteins from cells, in addition to several accessory proteins that dynein relies on. Following this, they combined these purified human proteins with purified HIV capsids (the containers holding the virus’s genetic material).

“This reconstitution system enables us to focus solely on the components we wish to analyze, devoid of any extraneous background interference from the complex cellular environment,” stated Cianfrocco, associate professor of biological chemistry at the U-M Medical School and a research associate professor at the LSI. “We arrange each component on a microscope slide alongside microtubules. Then, we observe their movement.”

With this method, the team discovered that HIV attaches directly to dynein, without the need for BicD2. However, another adaptor protein is required to activate dynein’s movement, but it can be any dynein adaptor protein—not exclusively BicD2.

Since various adaptor proteins are accessible in different cells, this adaptability enhances the virus’s chances of hitchhiking to the nucleus of any cell it has invaded, explains Somaye Badieyan, a research scientist in Cianfrocco’s lab who directed the study.

“This provides a fresh perspective on how the infection occurs,” she remarked. “It indicates that the virus is not reliant on a single specific type of adaptor to reach its destination. It’s a far more opportunistic hijacker than we had previously assumed.”

The study is the first instance of successful viral trafficking utilizing reconstituted components. Due to the fact that viruses cannot live or replicate outside of a host organism, researching them outside of the cellular environment has been a challenge. This novel approach now opens new pathways for studying viral infection, according to Cianfrocco.

“Having established this defined system, we can now progressively add different components one at a time to truly understand what is occurring at a more granular level,” he noted. “This study presents a new framework for considering direct viral attachment and provides a foundation for further probing into various directions.”

The research received support from the National Institutes of Health. In addition to Cianfrocco, the authors of the study include: Somayesadat Badieyan, Michael Andreas, John Gillies, Morgan DeSantis, and Tobias Giessen of U-M; Drew Lichon, Sevnur Komurlu Keceli, and Edward Campbell of Loyola University Chicago; Wang Peng and Till Böcking of the University of New South Wales, Australia; and Jiong Shi and Christopher Aiken of Vanderbilt University Medical.

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