Abstract
Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune evasion. Notably, the inability of Nef to down-regulate CD3 from infected T cells distinguishes HIV-1 Nef and its direct simian precursors from other primate lentiviruses. Why HIV-1 does not employ this potential immune evasion strategy is not fully understood. Using chimeric HIV-1 constructs expressing lentiviral Nef proteins that differ in their ability to down-modulate CD3, we show that retaining CD3 on the surface of infected primary T cells results in increased viral replication and cell-to-cell spread. We identified increased expression of envelope (Env) trimers at the cell surface and increased Env incorporation into virions as the determinants for the Nef- and CD3-dependent enhancement of viral infectivity. Importantly, this was independent of Nef-mediated antagonism of the host restriction factor SERINC5. CD3 retention on the surface of infected primary T cells also correlated with increased T cell signaling, activation, and cell death during cell-to-cell spread. Taken together, our results show that loss of an otherwise conserved function of Nef has a positive effect on HIV-1 replication, allowing for more efficient replication while potentially contributing to HIV-1 pathogenesis by triggering T cell activation and cell death during viral spread.
Highlights
Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1
Further in vitro analysis confirmed that the resulting retention of CD3 at the cell surface led to an increase in T cell activation and cell death following T cell receptor (TCR) cross-linking of infected CD4+ T cells [15, 16]
To test whether loss of Nefmediated CD3 down-regulation was associated with increased viral spread between T cells, we used a panel of previously described genetically engineered HIV-1 NL4.3 constructs coexpressing green fluorescent protein (GFP) and SIVsmm Nefs differing in this function from a bicistronic RNA [11, 16]
Summary
Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. Further in vitro analysis confirmed that the resulting retention of CD3 at the cell surface led to an increase in T cell activation and cell death following TCR cross-linking of infected CD4+ T cells [15, 16] Whether these mutations in Nef directly affected the viral replication cycle or conferred any replicative advantage to the virus that may explain their selection in vivo, and by extension provide new insights into the loss of this Nef function by the HIV-1 lineage, remained to be fully defined
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
