Lipid-mediated interplay between host restriction factor Serinc5 and HIV-1 ENV glycoprotein.

Abstract

Human immunodeficiency virus (HIV-1) is a pathogenic retrovirus that continues to be a severe threat to public health. HIV-1 is an enveloped virus that enters and infects cells through cell-virus membrane fusion, mediated by HIV-1 envelope glycoprotein, Env.The host restriction factor, Serinc5, impairs this process. It reduces HIV infection rates by incorporating itself into the viral membrane and blocking fusion of the virus with the plasma membrane of uninfected cells. The exact restriction mechanism of Serinc5 remains unknown. Studies suggest that Serinc5 disrupts Env distribution at the membrane and inhibits the protein's fusion function. We hypothesize that Serinc5 acts on Env by altering the physical properties of the surrounding membrane. In this study, we evaluate the nature of the membrane properties affected by Serinc5. Applying the fluorescent probe FLIPPER-TR to measure membrane order in viral particles with and without Serinc5, we discovered that Serinc5 slightly increases lipid order. HIV-1 bearing Env with a truncated cytoplasmic tail (∆CT) avoids infection restriction by Serinc5. We used isolated giant plasma membrane vesicles (GPMVs) to quantify Serinc5 and Env partitioning into specific lipid domains. Our results indicate that Serinc5 and Env partition into the liquid-disordered lipid domains of the plasma membrane. Interestingly, mutant Env ∆CT showed different lipid phase preferences than Serinc5 and wild-type Env. We discuss how these different lipid interactions might affect entry of progeny viruses into cells by membrane fusion.