Human Immunodeficiency Virus 1, more commonly known as HIV-1, is known for its amazing ability to evade the immune system. Scripps Research scientists and their collaborators have now discovered how our innate immune system – the body’s first line of rapid defense once morest foreign invaders – detects HIV-1, even when the virus is present in very small amounts.
The conclusions, published on July 8, 2022, in molecular cell, reveal the two-step molecular strategy that triggers the innate immune response into action when exposed to HIV-1. This finding might impact 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 delineates how the immune system can recognize a highly 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 the perspective of therapeutic potential, these findings open new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions to prevent HIV infection. »
The innate immune system is activated before the adaptive immune system, which is the body’s second line of defense and involves more specialized functions, such as the generation of antibodies. 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 a key signaling protein of the innate immune system that senses DNA floating around in a cell. If cGAS detects a foreign presence, it activates a molecular pathway to fight off the invader.
However, because HIV-1 is an RNA virus, it produces very little DNA – so little, in fact, that scientists have failed to understand how cGAS and the innate immune system are able to detect and respond to it. distinguish it from our own DNA.
Scripps Research scientists have discovered that the innate immune system requires a two-step safety check to activate once morest HIV-1. The first step involves an essential protein – polyglutamine-binding protein 1 (PQBP1) – recognizing the outer envelope of HIV-1 as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as a warning signal to invoke cGAS. Once the viral shell begins to disassemble, cGAS activates additional immune pathways once morest the virus.
The researchers were initially surprised to find that two steps are required for innate immune activation once morest HIV-1, since most other DNA-coding viruses only activate cGAS in one step. This is similar in 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 exploit the immune cascade that is initiated before the virus can begin replicating in the host cell, following PQBP1 has decorated the molecule.
“While the adaptive immune system has been central to HIV research and vaccine development, our findings clearly show the critical role the innate immune response plays in detecting the virus,” says Sunnie Yoh, PhD, first study author and senior executive. scientist in Chanda’s lab. “By modulating the narrow window of this two-step process – following PQBP1 has decorated the viral capsid and before the virus is able to insert into the host genome and replicate – it is possible to develop new vaccine strategies with adjuvant once morest HIV-1. »
By shedding light on how the innate immune system works, these findings also shed light on 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 cGAS inflammatory pathway. Researchers will continue to study how the innate immune system is involved in disease onset and progression, as well as how it discriminates between self and foreign cells.
In addition to Yoh and Chanda, the authors of the study, “Recognition of HIV-1 Capsid Licenses Innate Immune Response to Viral Infection,” include Na Rae Ahn and Heather Curry of Scripps Research; Joa?o I. Mamede of Northwestern University and Rush University Medical Center; Gianguido C. Cianci, Lacy M. Simons, Judd F. Hultquist, and Thomas J. Hope of Northwestern University; Derrick Lau, Andrew Tuckwell and Till Bo?cking from the University of New South Wales; Maria T Sañchez-Aparicio and Adolfo García-Sastre of the Icahn School of Medicine at Mount Sinai; Joshua Temple and Yong Xiong of Yale University; Nina V. Fuchs and Renate Ko?nig of Paul-Ehrlich-Institut; Stephanie Gambut of Rush University Medical Center; Laura Riva of Calibr; and Xin Yin from the Harbin Veterinary Research Institute.
Funding was provided by the National Institutes of Health’s NIAID, the Gilead Sciences Research Scholars Program in HIV, and the German Research Foundation.
