The human immunodeficiency virus 1, or HIV-1 as it is more often known, is renowned for its amazing capacity to subvert the immune system. Researchers at Scripps Research and associates have now discovered how the body’s innate immune system, which serves as its first line of fast defence against external invaders, can identify HIV-1 even in extremely low concentrations. The research was presented on July 8, 2022, and published in Molecular Cell. It reveals the two-step molecular mechanism that triggers the innate immune response when HIV-1 is present.
This discovery could impact drug development for HIV treatments and vaccines, as well as shape our 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,” 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 body’s secondary line of defence, the adaptive immune system, which performs more specialised tasks including producing antibodies, is activated after the innate immune system. The ability to distinguish between “self” (our own proteins and genetic information) and alien components is one of the innate immune system’s main functions (such as viruses or other pathogens). A crucial signalling molecule in the innate immune system that detects DNA floating in a cell is called cyclic GMP-AMP synthase (cGAS). In the event that cGAS does identify an intruder, it opens a molecular route to combat the threat.
However, because HIV-1 is an RNA virus, it produces so little DNA that researchers are unsure how cGAS and the innate immune system are able to recognise it and differentiate it from human DNA. The innate immune system has to pass a two-step security check before it can react against HIV-1, according to research from Scripps Research. A crucial protein called polyglutamine binding protein 1 (PQBP1) recognises the HIV-1 outer shell as soon as it enters the cell and before it can replicate. This is the first stage. The virus is subsequently covered and embellished by PQBP1, which serves as a call to action for cGAS. When the viral shell starts to fall apart, cGAS opens up more immune-related pathways that attack the virus.
Since most other DNA-encoding viruses only activate cGAS in one stage, the researchers were first shocked to discover that two processes are needed for innate immune activation against HIV-1. This idea is comparable to two-factor authentication methods that ask users to enter a password and then authenticate their identity by responding to an email.
This two-part method also makes it possible for vaccination strategies to take advantage of the immunological cascade that is started after PQBP1 has decorated the molecule, before the virus can begin to multiply in the host cell.
“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 results also provide light on how our bodies react to various autoimmune or neurodegenerative inflammatory disorders by explaining how the innate immune system functions. For instance, it has been demonstrated that PQBP1 interacts with tau, a protein that is dysregulated in Alzheimer’s disease, and that this interaction activates the same inflammatory cGAS pathway. The innate immune system’s role in illness initiation and progression, as well as how it distinguishes between own and foreign cells, will be further studied by the researchers.