A research group that includes members from the Paul-Ehrlich-Institut discovered how the immune system recognises HIV as foreign via a two-step mechanism.
The human immunodeficiency virus—HIV—belongs to the lentivirus family and causes AIDS, a slowly progressive immunodeficiency disease. An HIV infection is chronic because HIV bypasses the immunological defence mechanisms and the immune system cannot eliminate the infection.
However, the immune system seems to have the ability to detect HIV at an early stage, according to the results of a research network that includes the Paul-Ehrlich-Institut. HIV is an RNA virus, meaning that its genetic information is present in the form of RNA (ribonucleic acid) in the virus particles. After entering a cell, the virus makes a DNA (deoxyribonucleic acid) copy of its RNA and then integrates it into the genome of the infected host cell (chromosome). The viral genome integrated into the chromosome of the infected cells—the provirus—is treated by the cells like a normal cell gene. The virus genome then remains invisible to the host cell's internal defence system, which is normally able to recognise foreign RNA and DNA.
The research team identified a previously unknown two-step mechanism that makes the virus "visible". In the first step, the viral capsid structure is labelled with a marker by binding the cell's own polyglutamine-binding protein 1 (PQBP1). Another cell protein, the "cyclic GMP-AMP synthase", binds the existing complex and, in the second step, recognises the viral nucleic acid as soon as the conversion of the RNA into DNA has been initiated within the capsid. The recognition of two viral components, the viral protein structure and the viral genome, ensures that the subsequent activation of the immune system does not occur spontaneously by only one component and that the body's own structures, which are not infected, are not inadvertently attacked. If activation occurs after this double detection, a powerful and targeted inflammatory reaction is mediated.
The study illustrates how sensors in the cells can be directed via additional factors and control mechanisms to detect even small amounts or short-lived patterns (pathogen-associated molecular patterns, PAMPs) in pathogens. Other pathogens could also possibly be detected in a very targeted and efficient manner by following this concept.
We have discovered a mechanism that could potentially be used to strengthen immunological protection mechanisms against HIV.
Dr Renate König (Head of the "Cellular Aspects of Host-Pathogen Interactions" Research Group)
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, Gambut S, Simons LM, Hultquist JF, König R, Xiong Y, García-Sastre A, Böcking T, Hope TJ, Chanda SK (2022): Recognition of HIV-1 capsid by PQBP1 licenses an innate immune sensing of nascent HIV-1 DNA.
Mol Cell 82: 2871-2884.e6.