Study Identifies Viral Decision-Making Factors in Latent HIV Reservoirs

Controlling the viral reaction of cells latently infected with HIV may have implications for future drug treatments.

Research efforts have targeted latent HIV reservoirs as a potential way to guide future treatments. In a new study published in Cell Reports, the authors aimed to distinguish between uninfected cells and latently infected cells, with hopes that eradicating the latent reservoirs could lead to a cure for the disease.

In its latent state, the virus remains transcriptionally silent, but can spontaneously reactivate and trigger reinfection of the cell after treatment with antiretroviral therapy ends. Researchers have attempted to develop drug treatments that can both reactivate and remove cells with latent provirus. Challenges such as incomplete reactivation of non-inducible provirus, uncertainty regarding clearance or death of cells after latent reversal, and coupling of migration and reactivation of latently infected T cells have caused barriers to developing a successful strategy.

Another approach includes direct removal of the latent reservoir, but so far researchers have been unable to identify latent cells at low expression levels.

For the study, the researchers used a viral construct that contained a gene or a green fluorescent protein (GFP) that gets expressed when a cell reactivates. The time-lapse single-cell imaging allowed them to monitor single latent cell reactivation from their silent to their active states by calculating the mean fluorescence of GFP.

After calculating the size of reactivated cells, the researchers found that within a latent population, only larger host cells reactivate while the smaller cells remained silent or latent.

“Our results present a case of passive host-cell dominated viral decision-making, in which the virus is off when the infected cell is small and can only spontaneously reactivate in larger cell sizes,” Roy Dar, PhD, assistant professor at the University of Illinois, said in a press release about the findings.

Additionally, the study showed that the T-cells’ transition from latent to active is dependent on the cell cycle and can be modulated by drug treatments, which may have implications for future therapies. Strategies using host-cell size and cell cycle for monitoring and controlling latency could support drug treatments for HIV, the researchers wrote.

“We showed that you can use drug treatment to modulate a population of cells in and out of a specific cell cycle state in order to bias their viral reaction,” Dr Dar said in the release.

References

Bohn-Wippert K, Tevonian EN, Lu Y, et al. Cell Size-Based Decision-Making of a Viral Gene Circuit. Cell Reports. 2018. Doi: https://doi.org/10.1016/j.celrep.2018.12.009

Cell size and cell-cycle states play key decision-making roles in HIV [news release]. University of Illinois’ website. https://bioengineering.illinois.edu/news/article/29128. Accessed January 2, 2019.