The first line of defense against HIV-1 is a two-step process

Researchers have discovered the molecular mechanism by which the innate immune system recognizes HIV-1, potentially contributing to the development of future treatments.  

Scientists at Scripps Research Institute (CA, USA) have recently published a paper in Molecular Cell detailing the ability of the innate immune system to detect human immunodeficiency virus 1 (HIV-1). These findings not only contribute to drug and vaccine development to combat HIV-1 but also offer insights into how the innate immune response functions in other diseases. 

HIV-1 is a virus that actively attacks the immune system, making the body more susceptible to illnesses and infections that could be fatal. Luckily, the innate immune system (the body’s first line of defense) has the ability to recognize the virus and signal further immune responses. The innate immune system distinguishes between the ‘self’, our own genetic material and proteins, and invaders, like viruses and pathogens. It does so via a one-step cyclic GMP-AMP synthase (cGAS) signaling process, which senses the presence of DNA within cells. If something foreign is detected by cGAS, a molecular pathway is activated to fight it off. After the innate immune system, the adaptive immune system is activated, which involves specialized functions including mounting an antibody response. 

However, HIV-1 is an RNA virus, meaning that the innate immune system must use a different method to detect it. “This research delineates how the immune system can recognize a very cryptic virus, and then activate the downstream cascade that leads to immunological activation,” reported senior author Sumit Chanda.  

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The current study demonstrated that in order to trigger an immune response against HIV-1, the innate immune system undergoes a two-step process. First, an innate immune system protein – polyglutamine binding protein 1 (PQBP1) – must recognize the foreign HIV-1 outer shell before the virus has a chance to replicate. Second, PQBP1 must then coat the virus, which signals cGAS to ‘sound the alarm’ to mobilize a full immune response. These two steps were found to be essential for combating HIV-1, even though only one step is necessary for most DNA viruses.  

First author Sunnie Yoh explained: “While the adaptive immune system has been a main focus for HIV research and vaccine development, our discoveries clearly show the critical role the innate immune response plays in detecting the virus. In modulating the narrow window in this two-step process – after PQBP1 has decorated the viral capsid, and before the virus is able to insert itself into the host genome and replicate – there is the potential to develop novel adjuvanted vaccine strategies against HIV-1.” 

In addition to revolutionizing HIV-1 treatments, the current findings provide insight into possible treatment options for other autoimmune and neurodegenerative diseases. In Alzheimer’s disease, PQBP1 has been demonstrated to interact with tau to activate cGAS signaling and further immune responses. By understanding and focusing on the role that the innate immune system plays in disease onset, we may be able to develop novel treatments that target the virus at the point of PQBP1 coating before replication can occur.