Mechanisms of Immune Evasion by RSV Nonstructural Proteins

Human respiratory syncytial virus (hRSV) is a significant cause of lower respiratory tract infections in children under the age of 5, the elderly, and immunocompromised individuals, leading to millions of hospitalizations that also contribute to mortality. Prior exposure to hRSV affords little protection for subsequent infections and therefore individuals are susceptible to reinfection. Despite the substantial burden to global human health, there are limited effective and safe prophylactic and therapeutic options available. The hRSV genome encodes for two ORFs at the 3’ end, the multifunctional nonstructural proteins NS1 and NS2. These proteins are implicated in several functions, including immune antagonism.  However, the mechanisms by which NS1 and NS2 proteins modulate host responses remain incompletely defined. We recently solved the X-ray crystal structures of NS1 and NS2. These structures provide the molecular basis for function and have advanced our understanding of nonstructural protein interactions with host components. Consequences of host-viral interactions include direct inhibition of cytosolic pathogen sensors and binding to host nuclear transcriptional machinery to shape the immune response to infection. Insights from these studies also provide a basis to target NS1 and NS2 therapeutically, including opportunities to generate structure-guided mutant viruses as future vaccine candidates with altered host interactions through NS1 and NS2.