Retrovirus image could enable treatment breakthrough
By Stephanie Soucheray
In the three decades since scientists and doctors discovered the human immunodeficiency virus (HIV), the virus that causes AIDS, the medical understanding of the disease has gone from rudimentary to complex. No longer a mysterious death sentence, HIV is a chronic infection that can be managed with drug therapy. Still, researchers have noted that, like all viruses, HIV can mutate rapidly, rendering certain medications ineffective.
But now, University of Minnesota researchers Hideki Aihara, Zhiqi Yin, and Ke Shi, have, for the first time, produced a crystalline image of the Rous sarcoma virus (RSV) intasome. Having an image of the intasome is widely considered a breakthrough in retrovirus biology because it provides a structural picture for drug developers to work with as they create new therapies against HIV and other retroviruses.
“RSV is a close surrogate for HIV,” says Aihara, senior author of the paper detailing their work, published this spring in Nature. Aihara is an associate professor in the department of biochemistry, molecular biology, and biophysics. The work was done in collaboration with Cornell University and St. Louis University.
Like HIV, RSV is a retrovirus. Retroviruses are notorious for the insidious actions they take on their host: They can inject their genetic material into the host’s genome, integrating themselves into host DNA using intasomes, or proteins.
“Viruses are very elegant and efficient, I guess as a consequence of evolution,” says Aihara. “They have a very sophisticated way of hijacking cells, so finding out mechanisms and seeing the structure is a very exciting step that can provide insight into [HIV’s] biological process.”
It took more than eight years and one supercomputer to reproduce the image of the RSV intasome, says Aihara. First, he and his colleagues had to find a small and stable piece of RSV DNA and freeze it in crystalline form. Next, multiple x-rays were used to capture information about the shape and structure of the crystal sample. Finally, Aihara took loads of data to the Minnesota Supercomputer Institute, where high-powered computers calculated the structural biology of the crystalline sample. The crystalline sample yielded surprises.
“The way the virus uses its own machinery to integrate into the host is different than we thought,” says Aihara. Most viruses use four integrase molecules, or groups of proteins, to fuse the host’s and virus’s DNA together. RSV uses eight molecules.
“These structures can show us how to tip the balance in the fight against HIV,” says Reuben Harris, a U professor of biochemistry, molecular biology, and biophysics. “One first has to understand how integrase work before that information can be leveraged.”
"This current work is a true tour de force. Aihara’s lab accomplished what many other labs tried and failed to do.”
Harris says eventually Aihara’s work could help develop new antiviral drugs as well as make current drugs more precise and less toxic, so patients can take lower doses to get successful outcomes.
“This current work is a true tour de force,” says Harris. “Aihara’s lab accomplished what many other labs tried and failed to do from a structural biology and drug discovery point of view.”
Ultimately, Aihara says, his lab will attempt to produce an image of the structure of the HIV integrase. “With that information, we can stop viral replication. Our image, and an image of HIV, offers a more basic understanding of how the virus hijacks the host.”
Dr. Ashley Haase, head of the department of microbiology and immunology, has been researching HIV at the University for 30 years. He says Aihara’s work offers a rational basis for novel drug design. “We currently do not have drugs that are fully suppressive of the disease,” says Haase. For the last two decades, Haase has collaborated with Tim Schacker (M.D. ’87), director of the U’s Infectious Disease Clinic, on identifying and targeting HIV where it thrives in the body.
“Unlike what most people may think, most of the virus is not in the blood stream, but in the lymphoid tissue,” says Haase. Lymphoid tissue (including the spleen and the gut) is lined with follicles that act as holding cells for the virus. “If you stop therapy, the infection is back full blown in two weeks because the virus is in [the] follicles.”
Virus replication in the lymph system also induces inflammation and scarring in lymphoid tissues, which in turn compromises the body’s immune system. Eliminating this lymphoid fibrosis is the goal of Schacker’s work. He’s currently conducting a randomly controlled trial, the gold standard in scientific research, that looks at reducing the scarring and inflammation in the lymphoid cells as a way to increase the immune system’s ability to fight HIV. “We need to think about what HIV drugs are doing and where they’re doing it,” says Schacker.