Two-step verification is used by the immune system to protect against HIV — Science Daily


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HIV-1, also known as human immunodeficiency virus 1, is well-known for its remarkable ability to bypass the immune system. Scripps Research researchers and others have discovered how HIV-1 can be detected by the body’s innate immune system. This is the body’s first line defense against foreign invaders.

These findings were published July 8, 2022. Molecular CellThe molecular strategy, which activates the innate immunity response when HIV-1 is present in two steps, was discovered by. This discovery could influence drug development and vaccines against HIV-1, and it will also help us understand how the innate immune system is implicated in neurodegenerative disorders like Alzheimer’s.

Sumit Chanda (PhD), professor in the Department of Immunology and Microbiology said that this research demonstrates how the immune system can detect a very obscure virus and activate the downstream pathway that leads to immunological activation. “These findings offer new therapeutic possibilities for vaccines, adjuvants and other treatments that mimic the immune response. This will help to prevent HIV infection.”

The body’s secondary defense line, the adaptive immune system (which involves more specialized functions such as the generation of antibodies), activates the innate immune system before it activates the adaptive immune. The primary function of the innate immunity system is to recognize between “self” and foreign elements, such as viruses and other pathogens. The innate immune system’s key signaling protein, Cyclic GMPAMP-AMP synthase, senses DNA in cells. If cGAS detects a foreign presence it activates the molecular pathway to defeat the invader.

HIV-1, an RNA virus that causes HIV-1 to be a deadly infection, produces very low levels of DNA. This is why scientists are still unsure how cGAS or the innate immune systems can detect it and differentiate it from our DNA.

Scripps Research researchers discovered that HIV-1 activation requires two steps of security. The first is the recognition of the HIV-1 outer layer by a critical protein, polyglutamine binding Protein 1 (PQBP1). This protein recognizes HIV-1 as soon as it enters a cell, and before it can reproduce. PQBP1 covers and decorates the virus. This signals cGAS to activate. Once the virus shell has begun to break down, cGAS activates other immune-related pathways.

Researchers were initially shocked to discover that two steps were required for innate immune activation of HIV-1. Most other DNA-encoding viruses activate cGAS only in one step. Similar to two-factor authentication technologies, which require users to enter a password then reply to an email confirmation, this concept is similar to technologies that use two factor authentication.

This mechanism opens up the possibility of vaccination strategies that exploit the immune cascade, which is activated before the virus can replicate in the host cells.

“While HIV research has been focused on the adaptive immune system, our findings clearly demonstrate the critical role that the innate immune reaction plays in detecting and preventing the virus from entering the host,” said Sunnie Yoh PhD, senior scientist in Chanda’s lab and first author of the study. “Modulating the narrow window of this two-step process, after PQBP1 has decorated viral capsid and before the virus can insert itself into host genome and reproduce — is possible to develop novel adjuvanted vaccination strategies for HIV-1.”

These discoveries shed light on how the body responds to other neurodegenerative inflammatory or autoimmune diseases by shedding light onto the functioning of the innate immune system. PQBP1 was shown to interact with tau, the protein that is dysregulated in Alzheimer’s disease. It also activates the same inflammatory pathway cGAS. Researchers will continue to study how the innate immunity system plays a role in disease progression and onset, and how it differentiates between foreign and self-derived cells.

Yoh and Chanda are the authors of the study “Recognition HIV-1 Capsid Licences Innate Immune Response To Viral Infection.” Hope of Northwestern University; Derrick Lau, Andrew Tuckwell and Till Bo?cking of the University of New South Wales; Maria T Sa?nchez-Aparicio and Adolfo Garci?a-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-Institute; Ste?phanie Gambut of Rush University Medical Center; Laura Riva of Calibr; and Xin Yin of the Harbin Veterinary Research Institute.

Funding was provided through NIAID of National Institutes of Health, Gilead Sciences Research Scholars Program HIV, and the German Research Foundation.


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