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Understanding molecular mechanisms and pathogenic functions of Nef-like retrovirus infectivity factors

Final Report Summary - NEF-FACTORS (Understanding molecular mechanisms and pathogenic functions of Nef-like retrovirus infectivity factors)

The protein Nef of primate lentiviruses (HIV-1, HIV-2 and SIV) is crucial for sustained virus replication in the host and the development of AIDS. Nef plays a major role in maintaining HIV highly infectious, with a mechanism that has remained elusive. In addition to promoting virus infectivity, Nef was found to increase also virus resistance to neutralizing antibodies. The primary objective of this project was to unveil the mechanisms by which Nef alters the infectivity of retrovirus particles and protects them from neutralizing antibodies.
Our experiments first established that many cell lines, especially those of hematopoietic origin, express an unknown inhibitor of HIV, counteracted by Nef and by another protein derived from a different group of retroviruses (glycoGag, from gammaretroviruses). Using next generation sequencing, we investigated the transcriptional program of several human cell lines, to identify potential genes responsible for the inhibitory phenotype observed in hematopoietic-derived cells. We discovered that a multipass transmembrane cellular protein, called SERINC5, is a potent inhibitor of retroviruses. SERINC5 was found to be efficiently incorporated into retroviral particles and impair the ability of viruses to infect target cells, by interfering with their capacity to deliver their content into the cytoplasm. However, retroviruses have developed factors, such as Nef and glycoGag, which induce the cells to remove SERINC5 from their surface, resulting in the production of highly infectious progeny virus particles. Furthermore, we identified another virus (equine infectious anemia virus, EIAV) which has evolved a SERINC5 antagonizing factor (S2), indicating that SERINC5 plays a fundamental role in the interaction of the host with different viral pathogens. Importantly, SERINC5 was found not only to determine the requirement of Nef for optimal infectivity but also to modulate the susceptibility of HIV to neutralizing antibodies, indicating a multifaceted antiviral activity.
SERINC5 belongs to a group of five homologous genes in the human genome, which is highly conserved in evolution and has a yet unknown cellular function. Our studies established that the ability to inhibit the retrovirus infectivity is retained in all animal species and therefore is associated with an ancestral feature of the protein. In the attempt to better understand the core cellular function of SERINC genes, we have also established that SERINC proteins stimulate the expression of several secreted antimicrobial genes, indicating that these multipass transmembrane proteins play a broad and important role in the immune response against microbial pathogens.
The outcome of this research solves a 20-years long mystery by explaining why Nef is required for full infectivity of HIV-1 and identify a crucial player in the host immune response against microbes. Viral infections remain today a global threat and a socioeconomic burden. Currently, 36 million people worldwide live with HIV-1, a virus which continues to be responsible for more than 2 million infections and 1.1 million deaths every year. Neither a preventive vaccine nor a cure exists against HIV and other viral pathogens. Understanding the antiviral activity of SERINC proteins could, therefore, provide inspiration for the design of novel antimicrobial strategies since innovative drugs could be designed to enhance the anti-viral activity of SERINC5 or to impair the ability of viral pathogens to overcome its inhibitory effects. These results should raise further interest towards the fundamental research on infectious diseases, which remain a constant threat to humankind.
The fellow has established his research group (The Virus-Cell Interaction Group) at the University of Trento (Italy) and is continuing this research aimed at understanding the function of SERINC genes and developing novel antiviral strategies.
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