HIV Research Breakthroughs at Salk, Scripps

Even though COVID gets most of the headlines, researchers at both the Salk Institute and Scripps Research have made progress on a virus that still affects tens of millions of people globally – HIV.

On July 6, a team of scientists from the Salk Institute and Rutgers University announced that they had determined the molecular structure of HIV Pol, a protein that plays a key role in the late stages of HIV replication, or the process through which the virus propagates itself and spreads through the body. Determining the molecule’s structure helps answer longstanding questions about how the protein breaks itself apart to advance the replication process. The discovery, with was published in Science Advances, reveals a new vulnerability in the virus that could be targeted with drugs.  

“Structure informs function, and the insights we gained from visualizing the molecular architecture of Pol give us a new understanding of the mechanism by which HIV replicates,” said co-senior author Dmitry Lyumkis, assistant professor in the Laboratory of Genetics and Hearst Foundation developmental chair at Salk. 
 
Although it is too early to consider clinical developments for a new HIV treatment because there is no existing therapeutic that specifically targets HIV-1Pol, Lyumkis said, the finding has the biggest implication toward understanding HIV’s basic biology and replication cycle which could be used to devise better therapeutics.
 
“We do not have any therapeutics in line. However, we have the first atomic blueprint that, in principle, could be used to develop a therapeutic. There is potential,” Lyumkis added. “If the avenue is pursued, the most likely candidate would be a small molecule. It would take lots of basic research, including chemistry, structural biology, and functional measurements, in order to devise a real therapeutic.”
 
The Salk and Rutgers team used cryogenic electron microscopy, an imaging technique to which Lyumkis has made important contributions, to reveal the three-dimensional structure of the HIV pol protein molecule. This led to the discovery that Pol is a dimer, meaning it’s formed by two proteins bound together. The finding was a surprise because other similar viral proteins are single-protein assemblies.  
 
The group showed that in this two-sided structure, the protease component of Pol is “loosely tethered” to the reverse transcriptase component in a binding configuration that keeps the protease slightly flexible.

“It’s holding the protease at arm’s length, loosely, and we believe that gives the protease a little bit of movement, which in turn allows it to initiate the cutting of polyproteins that is a prerequisite for viral maturation,” said co-first author Dario Passos, a former researcher in Lyumkis’ lab at Salk.

 
“Current HIV treatments include multiple classes of inhibitors for all three enzymes, and the discovery also reveals a new vulnerability that could be targeted with drugs,” Passos added.
 
The authors say the discovery opens the door for important follow-up research, including studies of the structure of the larger and more complex polyprotein Gag-Pol, also involved in viral assembly, as well as taking a closer look at the role of integrase in assembling the mature form of the HIV virus during replication.  

Innate Detection of HIV
 
On July 8, scientists at Scripps Research announced another breakthrough on HIV – how our innate immune system – the body’s first line of quick defense in attacking foreign invaders – detects HIV-1, even when the virus is present in very small amounts.
 
The findings, published in Molecular Cell, reveal the two-step molecular strategy that jolts the innate immune response into action when exposed to HIV-1. This discovery could impact drug development for HIV treatments and vaccines, as well as shape understanding of how the innate immune response is implicated in other areas – including neurodegenerative disorders such as Alzheimer’s.
 
“This research delineates how the immune system can recognize a very cryptic virus, and then activate the downstream cascade that leads to immunological activation,” said Sumit Chanda, PhD, professor in the Scripps Research Department of Immunology and Microbiology.
 
“From a therapeutic potential perspective, these findings open up new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions for preventing HIV infection.”

Scripps scientists discovered that the innate immune system requires a two-step security check for it to activate against HIV-1 - a similar concept to technologies that use two-factor authentication, such as requiring users to enter a password and then respond to a confirmation email.
 
The first step involves an essential protein – polyglutamine binding protein 1 (PQBP1) – recognizing the HIV-1 outer shell as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert signal to summon cGAS. Once the viral shell begins to disassemble, cGAS activates additional immune-related pathways against the virus.
 
“While the adaptive immune system has been a main focus for HIV research and vaccine development, our discoveries clearly show the critical role the innate immune response plays in detecting the virus,” said Sunnie Yoh, PhD, first author of the study and senior staff scientist in Chanda’s lab. “In modulating the narrow window in this two-step process – after PQBP1 has decorated the viral capsid, and before the virus is able to insert itself into the host genome and replicate – there is the potential to develop novel adjuvanted vaccine strategies against HIV-1.”  

By shedding light on the workings of the innate immune system, these findings also show how our bodies respond to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau – the protein that becomes dysregulated in Alzheimer’s disease – and activate the same inflammatory cGAS pathway. The researchers will continue to investigate how the innate immune system is involved in disease onset and progression, as well as how it distinguishes between self and foreign cells.
 
Growing Market for HIV Therapies 

These breakthrough HIV studies come at a time when the global HIV drug market is expected to gain traction from increasing developments and improvements in antiviral therapies.
 
Last year, New York-based Evergreen Health received FDA approval for Cabenuva – the first complete and injectable regimen for HIV-1 infected adults that can be registered once every month.
 
According to a report by Fortune Business Insights titled, “HIV Drugs Market, 2021-2028,” the market for drug therapies like Cabenuva – or the kind that might come from the Salk and Scripps teams’ research – stood at $28.79 billion in 2020 and is projected to grow from $30.46 billion in 2021 to $45.58 billion in 2028 at a CAGR of 5.9%.
 
There are an estimated 40 million people worldwide with HIV and the cases are growing rapidly in regions such as Africa and other developing areas that are expected to drive the market for new HIV drugs, according to research by the World Health Organization.

Scripps Research
Founded: 1924
CEO: Peter Shultz
Business: Medical and scientific research institute
Headquarters: La Jolla
Employees: Over 2,400
Revenue: Over $320 million (2020)
Website: scripps.edu
Notable: Scripps Research holds over 1,100 U.S. patents.


Salk Institute for Biological Studies
Founded: 1960
President: Rusty Gage, PhD
Headquarters: La Jolla
Business: Research institute
Revenue: $168,102,950 (2020)
Employees: Over 850 researchers
Website: www.salk.edu
Notable: Since its inception, six Salk Institute researchers have been awarded the Nobel Prize.