Human immunodeficiency virus 1, better known as HIV-1, is known for its amazing ability to evade the immune system. Scripps Research scientists and collaborators have discovered how our innate immune system — the body’s first line of rapid defense against foreign invaders — detects HIV-1 even when the virus is present in very small amounts.
Conclusions published on July 8, 2022 Molecular cell, reveal a two-step molecular strategy that activates the innate immune response upon exposure to HIV-1. The discovery could affect the development of HIV drugs and vaccines, and shape our understanding of how the innate immune response is involved in other areas, including neurodegenerative diseases such as Alzheimer’s disease.
“This study shows how the immune system can recognize a highly cryptic virus and then activate a cascade that leads to immunological activation,” says Sumit Chanda, Ph.D., professor in the Department of Immunology and Microbiology. “In terms of therapeutic potential, these findings open new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions for HIV prevention.”
The innate immune system is activated before the adaptive immune system, which is the body’s secondary line of defense and includes more specialized functions such as antibody production. One of the main duties of the innate immune system is to recognize “self” (our own proteins and genetic material) and foreign elements (such as viruses or other pathogenic microorganisms). Cyclic GMP-AMP synthase (cGAS) is a key signaling protein in the innate immune system that senses DNA floating in the cell. When cGAS does detect a foreign presence, it activates a molecular pathway to fight the invader.
However, because HIV-1 is an RNA virus, it produces very little DNA – so little, in fact, that scientists do not understand how cGAS and the innate immune system are able to detect it and distinguish it from our own DNA.
Scientists at Scripps Research have found that the innate immune system requires a two-step safety check to be activated against HIV-1. The first step involves an essential protein – polyglutamine-binding protein 1 (PQBP1) – recognizing the outer envelope of HIV-1 once it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert signal to call cGAS. Once the viral envelope begins to break down, cGAS activates additional immune pathways against the virus.
The researchers were initially surprised to find that two steps are required to activate innate immunity against HIV-1, since most other DNA-encoding viruses activate cGAS in only one step. This is a similar concept to technologies that use two-factor authentication, such as requiring users to enter a password and then reply to a confirmation email.
This two-part mechanism also opens the door to vaccination approaches that could exploit an immune cascade that is initiated before the virus can start replicating in the host cell, after PQBP1 has decorated the molecule.
“While the adaptive immune system has been the primary focus of HIV research and vaccine development, our findings clearly show the important role that the innate immune response plays in virus detection,” said Sunny Yeo, Ph.D., the study’s first author and a senior research scientist in Chand’s lab. . “By modulating the narrow window in this two-step process—after PQBP1 has decorated the viral capsid and before the virus can integrate into the host genome and replicate—there is potential to develop new adjuvanted vaccine strategies against HIV-1.”
While shedding light on how the innate immune system works, these findings also shed light on how our body responds to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau – a protein dysregulated in Alzheimer’s disease – and activate the same cGAS inflammatory pathway. Researchers will continue to investigate how the innate immune system is involved in the onset and progression of disease, and how it differentiates between self and foreign cells.
In addition to Yoh and Chanda, authors of the study, Recognition of the HIV-1 Capsid Licenses the 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; Jangida S. Chanci, Lacey M. Simons, Judd F. Hultquist, and Thomas J. Hope of Northwestern University; Derrick Lau, Andrew Tuckwell and Till Bocking of the University of New South Wales; Maria T. Sanchez-Aparicio and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai; Joshua Temple and Yong Xiong of Yale University; Nina V. Fuchs and Renato Koenig of the Paul Ehrlich Institute; Stephanie Gambut of Rush University Medical Center; Laura Riva of Caliber; and Xin Yin of the Harbin Veterinary Research Institute.
Funding was provided by NIAID of the National Institutes of Health, the Gilead Sciences HIV Scholars Research Program, and the German Research Foundation.