Pioneering HIV Work Produces ‘Big Surprise,’ Nets Four-Year, $1.2 Million Grant

Human immunodeficiency viruses, or HIV, inside the body regulate a key genetic process to change how much virus is produced at any given time – possibly to evade attacks from the immune system, new research from the University of Virginia School of Medicine suggests.

The discovery sheds light on the HIV infection process and could open the door to new treatments. The findings show such promise that the National Institutes of Health’s Institute of General Medicine Sciences has awarded the U.Va. researchers a four-year, $1.2 million grant to explore the implications.

HIV is an elusive virus that is quick to mutate to escape the immune system. Even knowing how slippery the virus is, the U.Va. researchers were surprised to discover it has this previously unknown capability. They found that all of the viruses present in the blood exhibit similar levels of a key gene function that regulates RNA transport and viral replication. The levels of the gene function sometimes varied as the infection progressed over time, and from patient to patient, but in individual patients, the degree of function was similar across the viruses present at any one point.

“It was a big surprise to us that there seems to be this selection for a set level of this activity to be there. In some patients, it changed with time. In some patients it went up, and in other patients it went down,” said David Rekosh of U.Va.’s Myles H. Thaler Center for AIDS and Human Retrovirus Research. “What we don’t know yet is why, or what meaning this has for the infection. But what’s important about our study is the fact that the gene is changing in this way. This tells us that regulating it is important to the virus.”

Rekosh and U.Va.’s Dr. Marie-Louise Hammarskjold have been working on the gene, Rev, for more than two decades. They were among the early pioneers who discovered the fundamental mechanism of what it does and how it does it.

“When we first discovered this fact that HIV uses Rev to get RNA from out of the nucleus to the cytoplasm, very little was known about how that occurs in the cell,” Hammarskjold said. “There’s a lot of excitement now about RNA biology, and this was one of the first inklings of how interesting RNA biology could be.”

Their new study offers, they believe, an unprecedented in-depth look at how Rev evolves inside people. When they started the study, they weren’t certain it evolved at all. And if it changed, as HIV is prone to do, would there be any functional significance? The answer was yes. Their next step is to figure out how and why.

The researchers note that HIV uses a totally different genetic pathway for RNA transport compared with most cellular genes and many other retroviruses. “We don’t know why HIV, which is also a retrovirus, chooses a more complicated mechanism using a viral protein [Rev] ,” Hammarskjold said. “We think it’s because the virus wants to do something special that these other retroviruses can’t do.”

With their NIH grant funding, they plan to explore the implications of their new findings and what that could mean for people with HIV.

“We’re trying to ask the question: Why is this mechanism there to begin with, and what does it mean for an HIV infection?” Rekosh said. “That ultimately informs on what you can do about it. It helps us understand the infection process better. It may also help us understand more about how the virus escapes the immune system.

“We’re going to be exploring whether or not this plays a role in which viruses get transmitted from one patient to another and which viruses remain in the patient during drug suppression,” he said. “When patients are on antiretrovirals, the main problem is there is latent virus remaining that is reactivated if the drugs are taken away, precluding a cure. We have reason to believe Rev might have a role to play in viral latency.”

The researchers’ findings have been published online by the Journal of Virology and will appear in a forthcoming print edition. The article’s credited authors are Emily A. Sloan of U.Va.; Mary F. Kearney of the National Cancer Institute; Laurie R. Gray of U.Va.; Kathryn Anastos of the Albert Einstein College of Medicine; Eric S. Daar of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Joseph Margolick of Johns Hopkins; Frank Maldarelli of the National Cancer Institute; Hammarskjold and Rekosh.