Discovery of how HIV hedges its bets opens the door to new therapies

May 10, 2018, Gladstone Institutes
Credit: CC0 Public Domain

A stem cell is one with infinite possibilities. So, for decades, scientists have puzzled over how the cell chooses to keep being a stem cell and continue dividing, or specialize into a specific cell type, like a heart or brain cell.

The same type of decision is made by HIV. When the 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.

"Biology can hedge its bets in a similar way to how you might diversify financial investments," explained Leor S. Weinberger, Ph.D., the William and Ute Bowes Distinguished Professor and director of the Center for Cell Circuitry at the Gladstone Institutes. "Diversifying investments by placing some funds in high-risk, high-yield stocks and others in low-risk, low-yield savings accounts helps protect against volatility in the market. Similarly, HIV covers its bases in a volatile environment by generating both active and dormant infections."

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

The Virus Rigs the System to Its Advantage

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.

Weinberger's 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 Maike Hansen, postdoctoral scholar in Weinberger's laboratory and 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 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 Hansen. "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."

Weinberger's team used a combination of mathematical modeling, imaging, and genetics to show that this type of 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.

Unexplored Targets for HIV Cure Strategies

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 Weinberger, who is also a professor of pharmaceutical chemistry at UC San Francisco. "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 in gene expression and could explain how other biological decisions are stabilized.

The paper "A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization" was published by Cell on May 10, 2018.

Explore further: Study challenges 'shock and kill' approach to eliminating HIV

More information: Maike M.K. Hansen et al. A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization, Cell (2018). DOI: 10.1016/j.cell.2018.04.005

Related Stories

Study challenges 'shock and kill' approach to eliminating HIV

May 1, 2018
Researchers have provided new insight into the cellular processes behind the 'shock and kill' approach to curing HIV, which they say challenges the effectiveness of the treatment.

HIV latency is not an accident: It is a survival tactic employed by the virus

February 26, 2015
New research from the Gladstone Institutes for the first time provides strong evidence that HIV latency is controlled not by infected host cells, but by the virus itself. This fundamentally changes how scientists perceive ...

New method allows scientists to study how HIV persists

April 24, 2018
After 35 years of rigorous research, there is still no cure for HIV. Current drugs can be used to halt the infection, but fall short of reaching hidden reserves of dormant virus that can lurk for life within infected white ...

Researchers find novel approach to reactivate latent HIV

June 5, 2014
A team of scientists at the Gladstone Institutes has identified a new way to make latent HIV reveal itself, which could help overcome one of the biggest obstacles to finding a cure for HIV infection. They discovered that ...

Recommended for you

FRESH program combines basic science with social benefits for women at risk of HIV

September 14, 2018
A program established by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard is addressing the persistently elevated risk of HIV infection among young women in South Africa from ...

New study finds HIV outbreak in Indiana could have been prevented

September 13, 2018
An HIV outbreak among people who inject drugs in Indiana from 2011 to 2015 could have been avoided if the state's top health and elected officials had acted sooner on warnings, a new study by the Yale School of Public Health ...

Largest study of 'post-treatment controllers' reveals clues about HIV remission

September 13, 2018
Most HIV patients need to take daily anti-retroviral therapy—if they suspend treatment, HIV will rebound within 3-4 weeks. But clinical trials have revealed that a small fraction of patients can stop taking medications ...

Very few sexually active gay and bisexual men use prophylactic drug to prevent HIV transmission, study finds

September 12, 2018
Only 4 percent of sexually active gay and bisexual men in the United States use Truvada, a highly effective medication used to prevent the transmission of HIV, according to the results of a first-of-its-kind study.

Special antibodies could lead to HIV vaccine

September 10, 2018
Around one percent of people infected with HIV produce antibodies that block most strains of the virus. These broadly acting antibodies provide the key to developing an effective vaccine against HIV. Researchers from the ...

Researchers date 'hibernating' HIV strains

September 5, 2018
Researchers at the BC Centre for Excellence in HIV/AIDS (BC-CfE) and Simon Fraser University (SFU), in partnership with University of British Columbia (UBC) and Western University, have developed a novel way for dating "hibernating" ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.