hRBP-virion · Comprehensive identification of host factors involved in the early steps of HIV infection.

Comprehensive identification of host factors involved in the early steps of HIV infection.

RNA viruses represent a major health threat to humans and other living organisms. In particular, human immunodeficiency virus (HIV) is the second cause of death worldwide due to a single pathogen and currently 37 million people is infected. The high mutation rate of viral RNA genomes usually lead to rapid evolution, making difficult the development of effective antiviral treatments, vaccines and a final cure. Understanding how viruses interact with the host cell remain essential for the eventual discovery of complementary therapeutic strategies. RNA has a central role in virus biology, yet viral genomes encode only a few proteins able to interact with RNA. Hence, viruses exploit host RNA-binding proteins (RBPs) to accomplish their biological cycle. Although poorly explored until now, many of these RBPs are promising targets for host-based antiviral intervention. The participation of cellular RBPs in virus infection has been investigated for decades, mostly on a case-by-case basis. However, the universe of proteins enabled with RNA-binding activity has dramatically expanded in recent years. For these reasons, the complement of host RBPs involved in virus infection has remained largely unknown. To fill this gap, we aimed at (i) curating all the human RBPs that had previous links to infection using a tailored computational pipeline; and (ii) creating a novel system-wide method to study experimentally changes in the cellular RNA-binding proteome in response to infection, using a tractable and safe RNA virus model, called sindbis. Once established in sindbis virus, our methods were applied to study HIV infection. After HIV entry into the host cell, the RNA genome is reversed transcribed into DNA and imported into the nucleus to be integrated into the chromosome. Recent evidence showed that reverse transcription occurs inside the viral capsid shell. This implies that all proteins required for early viral RNA metabolism must be already contained within the capsid and are taken up in the producer cell (summary figure A). The main goal of this project was to define the scope of host RBPs packed within HIV capsids and their biological significance on the early steps of infection. Two major conclusions arise from this project: (i) hundreds of cellular RBPs are involved in virus infection and affect the infection outcome; and (ii) specific host RBPs are incorporated into HIV capsids and have essential roles in virus spread. Cellular RBPs are thus master regulators of viral replication and represent promising targets for host-based antiviral therapies.

Data: CORDIS, © European Union