Dr. Art Poon, assistant professor at the Schulich School of Medicine and Dentistry, in partnership with the BC Centre for Excellence in HIV/AIDS, Simon Fraser University and the University of British Columbia, has developed a new method for dating hibernating HIV strains within infected persons: an important step towards the development of an effective HIV cure.
The main purpose of their study was to understand how HIV is able to persist in the human body for decades, despite effective drug treatment that prevents the virus from spreading to other cells. HIV inserts itself onto the human genome, and in some cases the virus enters a latent state that makes the infected cell effectively invisible to the immune system. When the virus is not actively making copies of itself, there is also nothing for anti-HIV drugs to inhibit. This population of cells carrying latent HIV, called the “latent virus reservoir,” can persist for a long time — based on recent estimates, the reservoir can be expected to last a person’s entire life, even with effective anti-HIV drug treatment. If treatment is ever stopped, a new generation of virus is quickly re-established from the latent reservoir. This reservoir is the main reason why it is so difficult to cure an HIV infection. While modern drug treatments have restored a near-average life expectancy to people living with HIV, the long-lived reservoir means that they must stay on treatment for the rest of their lives.
“The objective of the study was to figure out what was going on [in the reservoir]. We want to be able to cure the infection, to eradicate viruses from this latent reservoir,” said Dr. Poon. “The main target of curing HIV is to eradicate those viruses, and to do that, we have to know our enemy.”
Previous studies that have sequenced HIV in the latent reservoir have found that these hibernating variants are diverse. Dr. Poon and his colleagues took this further by adapting methods from evolutionary biology to reconstruct what happens when copies of HIV entered the reservoir. HIV evolves so quickly that it is possible to reconstruct a “tree of life” relating different copies of the virus within one person.
When the virus genome integrates itself into the human genome, however, it no longer changes at the rate of HIV — it changes at the rate of our own genome. Compared to the rate of virus evolution, the integrated virus is at a standstill.
"If the rate of evolution is fairly constant then [we] can map the frozen lineages to different parts of the tree, and determine if the virus is from early stage of infection.” Dr. Poon said.
By sequencing and analyzing HIV genomes from blood samples provided for this study by individuals in BC, the team used their evolutionary model to discover that the reservoir is largely comprised of viruses from an early stage of infection. These viruses entered the latent reservoir and became “frozen” for 20 years or longer. The team was further able to determine that re-activated viruses sampled during treatment had origins spanning decades, which suggests that, if treatment was ever stopped, a new generation of viruses could come from the entire history of that person’s infection.
The study represents a key step in the transition between basic science and the development of an effective cure.
“There is still a significant amount of work [to get to] an effective cure, but we’re describing the target of the cure and that’s how this study is going to play a role,” Poon said.
The study was published on Sept. 18 in the Proceedings of the National Academy of Sciences of the United States of America.