University of Wisconsin-Madison scientists at the Institute of Molecular Virology have uncovered a clever strategy that HIV-1 uses to squeeze more viral particles out of every cell it infects. A recent research paper published in Proceedings of the National Academy of Sciences, shows that two HIV-1 proteins team up to slow normal cell division, turning infected cells into efficient, virus-producing machines.
“We’ve known for a long time that HIV infection can arrest the cell cycle. What has been puzzling for decades is why? Here we used live cell imaging to discover that HIV-1 targets the cell cycle in multiple ways that combine to amplify viral gene expression and keep single infected cells alive long enough to produce high levels of infectious virus.” said Prof. Nathan Sherer, who is an HIV-1 expert and led the study together with Asst. Prof. Aussie Suzuki, an expert in the cell cycle. If researchers can find ways to alter HIV’s manipulation of the cell-cycle, they may be able to limit viral production and develop new classes of HIV therapies.
The study focused on two HIV proteins, Virion Infectivity Factor (Vif) and Viral Protein R (Vpr). Previous work has found that these viral proteins affect the cell cycle, the internal timing system that tells cells when to copy their DNA and divide. The new study showed that the two proteins don’t just act independently, but that they coordinate their efforts. Using a variety of specialized techniques, including live imaging of single infected cell fates over several days, the UW researchers found that Vif and Vpr froze cells at distinct points in the cell cycle. When both proteins were expressed, the two coordinated to pause cell division at a point when HIV viruses were optimally produced, and kept individual cells alive in this arrested, productive state for multiple days.
Lead author of the study, Madison Bandini, a graduate student in the Cancer Biology Graduate Program, said, “Vif and Vpr work in concert to hold infected T cells in a pseudo-G1 state, where duplicated transcription sites support peak levels of viral gene expression and virion output.”
The authors predict that future HIV treatments could target cells held hostage by Vif and Vpr to promote their more rapid death and clearance by the immune system. By decoding one more trick in HIV’s playbook, the study brings researchers a step closer to halting a virus that affects over 40 million people worldwide and over 1 million living in the United States.
“The more we understand the ways that HIV-1 spreads, replicates, and causes disease, the better treatments and countermeasures we can develop. HIV affects millions of people worldwide and, in the U.S., costs our healthcare system billions of dollars annually. Even in Wisconsin, HIV treatment is estimated to cost more than $100 million annually.” added Prof. Sherer.
The Institute for Molecular Virology (IMV) is a Center administered by the University of Wisconsin-Madison Office of the Vice Chancellor for Research focused on uncovering how viruses replicate, evolve, and cause disease, developing strategies for prevention and treatment of viral infections, and harnesses viruses as tools to understand biological processes. The IMV is composed of a core group of faculty from across the UW-Madison campus with tenure homes in the Departments of Oncology, Biochemistry, Medical Microbiology & Immunology, and Plant Pathology. Housed in the Robert M. Bock Laboratories, IMV anchors a much broader network of over 40 virology-focused researchers across UW-Madison who make up the Madison Virology Collective.