The immune system uses two-step verification to defend against HIV

Human immunodeficiency virus 1, more commonly known as HIV-1, is known for its remarkable 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.

His findings, published on July 8, 2022, in molecular cell, revealing a two-step molecular strategy that jolts the innate immune response into action upon exposure to HIV-1. These discoveries could impact the development of drugs 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.

“This study illustrates how the immune system can recognize a very cryptic virus, and then activate a downstream cascade that leads to immunological 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 offer additional solutions to prevent HIV infection.”

The innate immune system is activated before the adaptive immune system, which is the body’s secondary line of defense that involves more specialized functions, such as producing antibodies. One of the main 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 in the innate immune system that senses DNA floating within cells. If cGAS detects the presence of a foreigner, it activates a molecular pathway to fight off the attacker.

However, because HIV-1 is an RNA virus, it produces very little DNA – so little, that scientists don’t yet understand 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 it against HIV-1. The first step involves an essential protein – polyglutamine-binding protein 1 (PQBP1) – recognizing HIV-1’s outer shell 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 unravel, cGAS activates additional immune-related pathways against the virus.

The investigators were initially surprised to find that two steps were required for activation of innate immunity against HIV-1, because most other DNA-coding viruses only activate cGAS in one step. This is a concept similar to technology that uses two-factor authentication, such as requiring the user to enter a password and then respond to a confirmation email.

This two-part mechanism also opens the door for vaccination approaches that could take advantage of the immune cascade that starts before the virus can start replicating in the host cell, after PQBP1 adorns the molecule.

“While the adaptive immune system has been a major focus for HIV research and vaccine development, our findings clearly demonstrate the important role of the innate immune response in detecting the virus,” said Sunnie Yoh, PhD, study first author and senior staff member. scientists at Chanda’s lab. “In modulating this 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 potential for developing novel adjuvant vaccine strategies against HIV-1.”

By explaining how the innate immune system works, the 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 – a protein that becomes disorganized in Alzheimer’s disease – and activate the same inflammatory cGAS pathway. Researchers will continue to investigate how the innate immune system is involved in the onset and progression of disease, as well as how to differentiate between self and foreign cells.

Source:

Scripps Penelitian Research Institute

Journal reference:

10.1016/j.molcel.2022.06.010

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