Eliminating the latent reservoir of HIV

December 06, 2018

A new study suggests that a genetic switch that causes latent HIV inside cells to begin to replicate can be manipulated to completely eradicate the virus from the human body. Cells harboring latent HIV are "invisible" to the natural defenses of the immune system.

The findings, which suggest a cure for HIV may be possible, are reported in the journal Proceedings of the National Academy of Sciences.

During infection, the DNA of HIV makes its way into the host cell's nucleus and integrates itself into the host genome. The Tat gene circuit is a key piece of HIV DNA that controls the HIV gene transcription and activation. When activated, it initiates a takeover of the cell's machinery to churn out new copies of the HIV virus, which eventually burst from the cell and infect neighboring cells. HIV-specific immune effector cells kill cells infected with HIV, but only when the cells are being used to produce more of the virus, meaning that the Tat gene circuit is switched on. In cells that are latently infected, the Tat gene circuit is off, and the cell goes about its normal business all the while harboring quiescent HIV.

"By targeting the Tat gene circuit with drugs or small molecules to activate it, we would be able to cause latently-infected cells to start producing more virus, and then they can be destroyed by the immune system," said Jie Liang, the Richard and Loan Hill Professor of Bioengineering in the University of Illinois at Chicago College of Engineering and a lead author of the paper. So far, there are no drugs successfully targeting this circuit.

People infected with the HIV virus can live relatively normal lives with exceedingly low or even undetectable viral loads thanks to powerful antiretroviral therapies that work to suppress viral replication. But even in people where the virus is undetectable, it doesn't mean it's completely absent. The HIV virus can hide in cells in an inactivated state, meaning it isn't actively replicating.

This is a dire situation and makes life-long antiretroviral therapy the only option for HIV infected patients.

"It is extremely difficult to flush latently-infected cells out of their latency," Liang said.

Techniques developed to reactivate latent HIV-infected cells so that they become susceptible to the body's natural immune response or to drug therapies have had mixed results -- mostly because the technique, known as "shock and kill," relies on a class of drugs called HDAC inhibitors that come with severe adverse effects.

"We need to better understand the mechanisms that regulate HIV latency so we can identify new opportunities for intervention and develop better drugs that can either lock viral particles in a latent state, or kill latent cells, or both," Liang said.

The Tat gene circuit has a random probability of being active or inactive, and the switch from inactive to active can happen spontaneously. "In HIV-infected cells, reactivation of the Tat gene circuit is still a very rare event," Liang said.

Liang and his colleagues developed advanced computational algorithms to study the Tat gene circuit under different conditions.

"Using different models and algorithms, we were able to accurately map a 'probability landscape' of the cellular reactions that can impact Tat gene circuit reactivation, and our results suggest new ways of targeting latent cells that may lead to the eradication of the HIV virus from a host," Liang said.

Liang and his colleagues identified ways to manipulate the Tat gene circuit so that the "shock and kill" technique would be more effective. They also looked at a "block and lock" strategy, where latent viral particles are locked into latency by permanently blocking activation of the Tat gene circuit.

"Our results suggest that by controlling HIV latency through manipulation of the Tat gene circuit, effective therapeutic strategies can be identified that would one day provide a cure for HIV," Liang said.
-end-
Liang and Youfang Cao of Merck Research Laboratories are the lead authors of the study. Xue Lei from the University of Illinois at Chicago; and Alan S. Perelson and Ruy M. Ribeiro from the Los Alamos National Laboratory are the collaborators and co-authors on the paper.

This research was supported in part by contract DE-AC52-06NA5396 from the U.S. Department of Energy; grants R01-CA204962, R01-GM126558, R01-AI028433 and R01-OD011095 from the National Institutes of Health; and by the Center for Nonlinear Studies at the Los Alamos National Laboratory.

University of Illinois at Chicago

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.