2-step molecular strategy spots HIV-1

By The Science Advisory Board staff writers

July 11, 2022 -- Scripps Research scientists and collaborators have discovered the innate immune system uses a two-step molecular strategy to detect HIV-1, even when the virus is present in very small amounts.

The innate immune system is activated before the adaptive immune system and recognizes "self" and foreign elements. Cyclic GMP-AMP synthase (cGAS) is a signaling protein in the innate immune system that senses DNA floating in a cell and can activate a molecular pathway to fight off the invader. Because HIV-1 is an RNA virus, it produces very little DNA and scientists were stumped as to how cGAS and the innate immune system are able to detect it -- until now.

Scripps Research scientists found that a two-step process activates against HIV-1. The essential protein polyglutamine binding protein 1 (PQBP1) recognizes the HIV-1 outer shell as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert for cGAS. Once the viral shell begins to break apart, cGAS activates additional immune-related pathways against the virus (Molecular Cell, July 8, 2022).

Understanding this mechanism opens the door for vaccination approaches that can use the immune cascade before the virus can start to replicate in the host cell, after PQBP1 has decorated the molecule.

The team plans to continue investigating the innate immune system in terms of disease onset and progression, as well as how it distinguishes between self and foreign cells.

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