Study: HIV is a flexible cellular hijacker

​​University of Michigan researchers have uncovered new details of the process that HIV uses to hijack cells’ transportation systems for its own survival.

In addition to overturning a decades-old theory, the study offers a new system for probing specific components of viruses outside of the cellular environment to better understand mechanisms underlying infection and potentially identify new drug targets.

The insides of cells are not static environments. Specialized subunits of the cell are continuously on the move to perform activities that keep the cell operating. This intercellular transportation occurs on motor proteins that function like delivery trucks, loading cargo and moving it along microtubules, the cell’s highways.

HIV, or human immunodeficiency virus, takes advantage of this transportation system to get where it wants to go within host cells. By latching onto the delivery trucks called dynein, the virus catches a ride from the cell’s periphery toward the nucleus, where it integrates its own genetic material into the host cell’s genome to replicate.

Since the early 2000s, researchers have believed that HIV is able to board dynein only with the help of a cargo adaptor protein, which acts as a sort of trailer hitch between the virus and the motor protein. Later studies suggested that an adaptor protein called BicD2 was specifically necessary to link HIV to dynein.

A new study from the U-M Life Sciences Institute, published in Science Advances, has now reversed that theory, revealing that the virus can be much more flexible in its choice of travel companions.

A team from the lab of biochemist Michael Cianfrocco at the LSI developed a way to examine HIV trafficking outside of the cell. They purified dynein motor proteins from cells, along with a few accessory proteins that dynein depends upon. Then they combined those purified human proteins with purified HIV capsids (the container that holds the virus’s genetic material).

This reconstitution system allows us to view just the pieces we want to investigate, without any other background noise from the complex environment of the cell. We combine each piece on a microscope slide with microtubules. And then, we watch them walk.”

Michael Cianfrocco, associate professor of biological chemistry, U-M Medical School and research associate professor at the LSI

Using this approach, the team discovered that HIV hitches to dynein by attaching directly to the motor protein, not via BicD2. The motor protein does not start moving right away, though. Another adaptor protein does have to connect to a dynein to make it start walking, but it can be any dynein adaptor protein—not just BicD2.

Because different adaptor proteins are available in different cells, this flexibility expands the virus’s options for hitchhiking to the nucleus of whichever cell it has gained access to, says Somaye Badieyan, a research scientist in Cianfrocco’s lab who led the study.

“This opens a new perspective on how the infection is happening,” she said. “It means that the virus doesn’t have to wait for just one specific type of adaptor to get where it needs to go. It’s a much more opportunistic hijacker than we previously thought.”

The study represents the first example of successful viral trafficking using reconstituted components. Because viruses cannot survive or replicate without a host organism, studying them outside of the cellular environment has been challenging. This approach now opens new avenues for investigating viral infection, Cianfrocco says.

“Now that we have achieved this defined system, we can continue adding different components one at a time to really figure out what is happening on an even more detailed level,” he said. “This study introduces a new way to think about direct viral attachment, and gives us the platform to start probing in even more directions.”

The research was supported by the National Institutes of Health. In addition to Cianfrocco, study authors are: 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.