Human Immunodeficiency Virus 1, more commonly known as HIV-1, is known for its uncanny ability to evade the immune system. Scientists at Scripps Research and collaborators have now discovered how our innate immune system — the body’s first line of defense against foreign invaders — detects HIV-1 even when the virus is present in very small amounts.
The findings, published on July 8, 2022, in Molecular cell, reveal the two-step molecular strategy that triggers the innate immune response when exposed to HIV-1. This discovery could influence drug development for HIV treatments and vaccines, as well as shape our understanding of how the innate immune response is involved in other areas, including neurodegenerative disorders such as Alzheimer’s disease.
“This research outlines how the immune system can recognize a highly cryptic virus and then activate the downstream cascade that leads to immunologic activation,” said Sumit Chanda, PhD, professor in the Department of Immunology and Microbiology. “From a therapeutic potential perspective, these findings open new avenues for vaccines and adjuvants that mimic the immune response and provide complementary solutions for preventing HIV infection.”
The innate immune system is activated before the adaptive immune system, the body’s secondary line of defense that includes more specialized functions, such as antibody generation. One of the primary responsibilities of the innate immune system is to recognize between ‘self’ (our own proteins and genetic material) and foreign elements (such as viruses or other pathogens). Cyclic GMP-AMP synthase (cGAS) is an important signaling protein in the innate immune system that senses DNA floating inside a cell. When cGAS detects a foreign presence, it activates a molecular pathway to fight the invader.
However, because HIV-1 is an RNA virus, it produces very little DNA — so little, in fact, that scientists haven’t understood how cGAS and the innate immune system can detect it and distinguish it from our own DNA.
Scripps Research scientists found that the innate immune system requires a two-step safety check to activate against HIV-1. The first step involves an essential protein – polyglutamine binding protein 1 (PQBP1) – that recognizes the outer shell of HIV-1 once it enters the cell and before it can replicate. PQBP1 then coats and embellishes the virus and acts as a warning signal to evoke cGAS. Once the viral shell begins to decompose, cGAS activates additional immune-related pathways against the virus.
The researchers were initially surprised to find that two steps are required for innate immune activation against HIV-1, since most other DNA-coding viruses activate cGAS in only one step. This is 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.
This two-part mechanism also opens the door to vaccination approaches that can take advantage of the immune cascade that is initiated before the virus can begin to replicate in the host cell, after PQBP1 has decorated the molecule.
“While the adaptive immune system has been one of the main focuses for HIV research and vaccine development, our discoveries clearly demonstrate the critical role the innate immune response plays in detecting the virus,” said Sunnie Yoh, PhD, lead author of the study and senior staff. scientist in Chanda’s lab. “By modulating the narrow window in this two-step process — after PQBP1 has adorned the viral capsid and before the virus can 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 how the innate immune system works, these findings also illuminate 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 activates the same inflammatory cGAS pathway. The researchers will continue to investigate how the innate immune system is involved in disease onset and progression, and how it distinguishes between its own and foreign cells.
Scripps Research Institute
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