Human immunodeficiency virus 1, more commonly known as HIV-1, is known for its ability to evade the immune system. Scientists at Scripps Research and collaborators have revealed how our innate immune system detects HIV-1, even when the virus is present in very small amounts. Their findings could lead to the development for HIV treatments and vaccines.

The findings are published in Molecular Cell in a paper entitled “Recognition of HIV-1 capsid by PQBP1 licenses an innate immune sensing of nascent HIV-1 DNA.”

“We have previously described polyglutamine-binding protein 1 (PQBP1) as an adapter required for the cyclic GMP-AMP synthase (cGAS)-mediated innate response to the human immunodeficiency virus 1 (HIV-1) and other lentiviruses,” wrote the scientists.

“This research delineates how the immune system can recognize a very cryptic virus, and then activate the downstream cascade that leads to immunological activation,” says Sumit Chanda, PhD, professor in the 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.”

The scientists discovered that the innate immune system requires a two-factor authentication strategy for it to activate against HIV-1. 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,” says 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.”

These findings reveal how our bodies respond to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau 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.