When the virus infects a cell, it can either turn on and start multiplying, or turn off so it can hide in the cell until a later date.

But if HIV is randomly switching between these two fates, how does it ever commit to remaining in one state? The laboratory has now answered this longstanding question and potentially uncovered how biological systems make such decisions. Their findings are published in the journal Cell.

HIV benefits from maintaining both an active state and a dormant, or latent, state.

The active state allows the virus to spread and infect more cells, whereas virus in the latent state can survive in hiding for long periods of time. While the active virus can be killed by antiviral drugs, latent virus lies in wait and can rapidly reactivate when drugs are stopped. Because the latent virus cannot be treated by current therapies, it represents the main obstacle to curing HIV.

The team previously showed that HIV generates these two categories of infection by exploiting random fluctuations in gene expression.

"Even when two cells are genetically identical, one can produce a large amount of a protein, while the other can produce a much smaller amount," said one of the first authors of the study. "These random fluctuations, called noise, can determine the fate and function of the cell. HIV uses noise to create both active and latent virus."

To express its genes, HIV uses a mechanism known as alternative splicing, which essentially allows the virus to cut up parts of its genome and arrange them in different combinations. By observing individual cells over time, the researchers discovered that HIV hijacks an exotic form of splicing to tune random noise. This tuning of noise dictates whether the virus will remain stably active or latent.

"We found that HIV uses a particularly inefficient form of splicing to control noise," added the author. "Surprisingly, if it worked efficiently, this mechanism would produce much less active virus. But, by seemingly wasting energy through an inefficient process, HIV can actually better control its decision to remain active."

The team used a combination of mathematical modeling, imaging, and genetics to show that this type of alternative splicing occurs after transcription, during which genetic information in DNA is copied into a molecule called RNA. Previously, scientists thought that splicing occurred at the same time as transcription. This study represents the first function for post-transcriptional splicing.

Feedback is established through a serial cascade of post-transcriptional splicing, whereby proteins generated from spliced mRNAs auto-deplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV’s commitment decision, and a noise-suppression molecule promotes stabilization.

The study demonstrates that HIV conserved a highly inefficient process on purpose, and by correcting it, scientists could significantly harm the virus. These findings could reveal unexplored targets for the development of novel HIV cure strategies.

"The splicing circuit may give us an opportunity to therapeutically attack the virus in a different way," said the senior author. "For a while, there have been proposals to 'lock' HIV in latency and 'block' it from reactivating, but how to do this wasn't clear."

Researchers may now be able to continually force HIV back into latency by exploiting the virus's splicing circuit and achieve the "lock and block" therapy.

By revealing a new fundamental mechanism, this study also has broader implications in biology. Inefficient splicing likely occurs in 10-20 percent of genes. So, this circuitry may be generally employed to minimize random fluctuations in gene expression and could explain how other biological decisions are stabilized.

https://gladstone.org/about-us/press-releases/discovery-how-hiv-hedges-its-bets-opens-door-new-therapies

https://www.cell.com/cell/fulltext/S0092-8674(18)30458-6