The human immunodeficiency virus (HIV) has developed mechanisms to evade early detection by the innate immune system.
A research association involving the Paul Ehrlich Institute has identified a mechanism with which the immune system is in principle also able to recognize HIV-1.
Understanding this mechanism could be helpful for the development of AIDS vaccines.
In an international research network, researchers at the Paul Ehrlich Institute have discovered a two-stage mechanism of the innate immune system that makes it possible to specifically recognize the HI virus (human immunodeficiency virus, HIV) and trigger an early immune response. This knowledge could be used in the development of vaccines that enhance this mechanism and thus create an effective and early endogenous defense against HIV. Molecular Cell reports on the results in its online edition of July 8th, 2022.
The human immunodeficiency virus HIV-1 belongs to the family of the so-called lentiviruses, which poses particular challenges to medicine. HI viruses cause AIDS, a slowly progressing, chronic infectious disease, because they are able to bypass the defense mechanisms of the immune system.
International research network can elucidate the mechanism by which HIV escapes the immune system
However, the immune system seems to have the fundamental ability to detect HIV at an early stage. Researchers from the Paul Ehrlich Institute, in an international research network headed by Dr. Chanda and Dr. Yoh, Sanford Burnham Preby’s Medical Discovery Institute in La Jolla, California, along with colleagues from New York, Chicago, Sydney and New Haven. They were able to elucidate the mechanism by which the genetic information, the DNA of the HI virus, is recognized as foreign in the cell and a defense can be triggered as a result. The HI virus is an RNA virus. After entering a cell, the HI virus synthesizes a single copy of DNA from the RNA genome and then integrates it into the host’s genome. It is treated by the cell like a normal cell gene and thus remains invisible to the host’s defense system.
Two-step mechanism makes the smallest amounts of foreign DNA visible
Now how can the cellular surveillance machinery detect this small amount of DNA, even if it is transient? The scientists identified a previously unknown two-step mechanism that makes this possible. A receptor – already identified in 2015 – the protein polyglutamine binding protein 1 (PQBP1) marks the intact viral capsid in a first step. The capsid is the protein structure that serves to package the viral genome. The already known DNA sensor protein, the so-called cyclic GMP-AMP synthase (cGAS), is required in the second step when the HI virus converts its RNA into DNA during the reverse transcription process and the viral capsid begins to disintegrate .
This two-stage recognition of both pathogen protein (HIV capsid) and pathogen DNA (HIV DNA) ensures that the subsequent activation of immune-stimulating signaling pathways (via interferon, IFN) is not activated spontaneously by just one component. This ensures that the body’s own structures are not accidentally attacked. When activated after this dual recognition, a strong and targeted inflammatory response is mediated. This elicits a robust response to “true” foreign DNA species while circumventing unwanted self-activation of host DNA.
New knowledge beyond innate cellular recognition of lentiviruses
The collaborative study not only provides new insights into the innate cellular recognition of viruses from the lentivirus family, but also illustrates how sensors in the cells, via additional factors and control mechanisms, respond to specific and possibly rare or transiently available microbial patterns (pathogen- associated molecular patterns, PAMPs) can be controlled. With this general concept, other pathogens could possibly also be identified very specifically and efficiently.
Originalpublikation
Yoh SM, Mamede JI, Lau D, Ahn N, Sánchez-Aparicio MT, Temple J, Tuckwell A, Fuchs NV, Cianci GC, Riva L, Curry H, Yin X, Gabut S, Simons LM, Hultquist JF, König R (2022): Recognition of HIV-1 capsid by PQBP1 licenses an innate immune sensing of nascent HIV-1 DNA.
Mol Cell Jul 8 [Epub ahead of print].
Online-Abstract
Further information
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