Discovery reveals how cells try to control levels of key HIV protein

May 31, 2018, Salk Institute
Salk scientists uncover potential new targets for antiviral drugs using novel laboratory method. From left: Muyu Xu and Katherine Jones Credit: Salk Institute

One of the many challenges in treating HIV is that the virus can lie dormant in cells, quietly evading immune detection until it suddenly roars to life without warning and begins replicating furiously. Salk Institute researchers discovered a small molecule called JIB-04 that destroys the HIV protein called Tat, responsible for revving up the virus.

The molecule, while itself too toxic to serve as a therapy for HIV, reveals proteins in host cells that can potentially target Tat and halt this runaway replication process. The work, which appeared in the journal PLOS Pathogens on May 23, 2018, also more broadly illustrates a powerful new laboratory technique that can identify more precisely which proteins bind to drugs—information that is often elusive.

"The level of Tat very much determines whether or not you can reactivate a virus from latency," says senior author Katherine Jones, a professor in Salk's Regulatory Biology Laboratory and holder of the Edwin K. Hunter Chair. "Even though JIB-04 cannot be used clinically, we were able to use it to show an important part of how Tat levels are determined by a pair of enzymes in the . Identifying them offers new targets for potential therapies."

Like all viruses, HIV-1 (the common form of HIV) enters the body and uses the host's own cellular machinery to copy the viral genetic material and spread from cell to cell. Tat kicks copying into high gear when conditions are favorable, revving up the machinery a thousandfold. Jones' team was investigating other HIV proteins when they noticed that one of the compounds they were testing, a small molecule called JIB-04, caused Tat to disappear.

The effect was striking, but how exactly JIB-04 was accomplishing this vanishing act was unclear. Jones enlisted the help of researcher James Moresco, director of Salk's Mass Spectrometry Core, who used a new approach called DiffPOP (short for "differential precipitation of proteins") to identify the protein targets of drug compounds.

"The application of the DiffPOP technique to identify drug/ interactions enabled the identification of a completely unexpected insight into the biology of HIV," says Moresco. "It is a great example of how collaboration between our labs at Salk, as well as with The Scripps Research Institute, who developed the underlying technology, encourages discovery."

The DiffPOP results showed that JIB-04 was binding to two of the host cells' enzymes (SHMT2 and BRCC36) whose job is to rescue proteins that have been targeted for disposal. Some enzymes flag proteins as cellular "trash"; others remove the flags, thereby saving those proteins from destruction. Jones' team hypothesized that the compound interfered with the ability of these proteins to protect Tat, enabling the cell to destroy Tat and keep the virus in its latent state.

Further tests confirmed their hypothesis: in cells not treated with JIB-04, but in which the two enzymes were disabled through molecular methods, Tat levels also went down. Additionally, in cells that were treated with JIB-04 as well as ones in which the two enzymes were disabled, Tat was flagged for degradation at high levels, which also suggested that the enzymes were responsible for flag removal.

"Based on these phenomena, we think this compound may actually target these two proteins," says Muyu Xu, a research associate at Salk and the paper's first author. "It may have other potential targets, but this pair is one of them. So we concluded that these enzymes might be novel factors that regulate Tat turnover in ."

Even though HIV has gone from a deadly disease to a chronic condition that can be kept at bay with antiviral therapies, the daily cocktail of drugs is extremely burdensome for people with the disease. The researchers say that understanding the factors that influence Tat's stability are crucial to being able to control the virus.

"As researchers, we'd like to find a way for people not to have to be on these drugs their whole lives," says Jones. "So the idea of inhibiting Tat to get to a functional cure for HIV is very appealing."

Explore further: Scientists identify a promising target for HIV/AIDS treatment

More information: Muyu Xu et al. SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy, PLOS Pathogens (2018). DOI: 10.1371/journal.ppat.1007071

Related Stories

Scientists identify a promising target for HIV/AIDS treatment

October 24, 2014
Like a slumbering dragon, HIV can lay dormant in a person's cells for years, evading medical treatments only to wake up and strike at a later time, quickly replicating itself and destroying the immune system.

Discovering crucial role of protein that could stop HPV virus infection

April 30, 2018
New drugs in the early stages of development by pharmaceutical companies could have an extra benefit – the ability to cancel out HPV virus, which can cause cervical cancer and skin conditions.

Novel genome platform reveals new HIV targets

February 27, 2018
Sanford Burnham Prebys Medical Discovery Institute (SBP) researchers have developed the first ever high-throughput, genome-scale imaging-based approach to investigate protein stability. The method has been used to identify ...

Scientists identify genes that could inform novel therapies for EBV-related cancers

March 20, 2018
VCU Massey Cancer Center researchers have identified two genes that are responsible for governing the replication of the Epstein-Barr virus, an infection that drives the growth of several types of cancer. The discovery could ...

Scientists established a comprehensive protein interactions map of the replication machinery of a chronic virus

December 20, 2017
Chronic viral infections like HIV or hepatitis are among the biggest threats to human health worldwide. While an acute viral infection usually results in full recovery and effective immune memory, chronic viruses evade the ...

Recommended for you

New simulation tool predicts how well HIV-prophylaxis will work

June 14, 2018
A new mathematical simulation approach predicts the efficacy of pre- and post-exposure prophylaxis (PrEP) medications, which help prevent HIV infection. The framework, presented in PLOS Computational Biology by Sulav Duwal ...

Many at risk for HIV despite lifesaving pill

June 11, 2018
Multiple barriers may stop high-risk individuals from accessing an HIV drug that can reduce the subsequent risk of infection, according to a new University of Michigan study.

Active HIV in large white blood cells may drive cognitive impairment in infected mice

June 7, 2018
Macrophages, large white blood cells that engulf and destroy potential pathogens, harbor active viral reserves that appear to play a key role in impaired learning and memory in mice infected with a rodent version of HIV. ...

HIV vaccine elicits antibodies in animals that neutralize dozens of HIV strains

June 4, 2018
An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported ...

HIV study reveals new group of men at risk of infection

June 4, 2018
A group of men who may be underestimating their HIV risk has been identified in a new study.

Discovery reveals how cells try to control levels of key HIV protein

May 31, 2018
One of the many challenges in treating HIV is that the virus can lie dormant in cells, quietly evading immune detection until it suddenly roars to life without warning and begins replicating furiously. Salk Institute researchers ...


Adjust slider to filter visible comments by rank

Display comments: newest first

4 / 5 (1) Jun 05, 2018

I started using multiple sclerosis (MS) herbal remedy i purchased from Best Health Herbal Centre January this year. I only used it for a month and two weeks, my condition changed automatically, all my symptoms are gone. Remaining positive have helped me during this treatment. Now am living MS FREE.
Hope this will help somebody, remember, do your own research and make your own decisions based on information you have received and digested. Thanks to Best Health Herbal Centre for their amazing work. Forever Grateful!
Contact them via w ww .besthealthherbalcentre. com
not rated yet Jun 05, 2018
My name is Mahmooda Sayed, I am from Texas,USA. I am sure this information will be useful to the general public on how my sister was cured from Genetic Herpes with the same herbal practitioner who also got me cured from HIV/AIDS,The medication was administered by Dr Zulu. He cures other diseases too. For further information visit, For those of us that would come back appreciating me or might need further information, the above name is my Facebook name or you can also write me mails at

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.