Retromer regulates HIV-1 envelope glycoprotein trafficking and incorporation into virions.
The envelope glycoprotein (Env) of the Human Immunodeficiency Virus Type-1 (HIV-1) is a critical determinant of viral infectivity, tropism and is the main target for humoral immunity; however, little is known about the cellular machinery that directs Env trafficking and its incorporation into nascent virions. Here we identify the mammalian retromer complex as a novel and important cellular factor regulating Env trafficking. Retromer mediates endosomal sorting and is most closely associated with endosome-to-Golgi transport. Consistent with this function, inactivating retromer using RNAi targeting the cargo selective trimer complex inhibited retrograde trafficking of endocytosed Env to the Golgi. Notably, in HIV-1 infected cells, inactivating retromer modulated plasma membrane expression of Env, along with Env incorporation into virions and particle infectivity. Mutagenesis studies coupled with coimmunoprecipitations revealed that retromer-mediated trafficking requires the Env cytoplasmic tail that we show binds directly to retromer components Vps35 and Vps26. Taken together these results provide novel insight into regulation of HIV-1 Env trafficking and infectious HIV-1 morphogenesis and show for the first time a role for retromer in the late-steps of viral replication and assembly of a virus.
Division of Infection and Immunity, University College London, London, United Kingdom.
Elisabetta
E
Groppelli
Division of Infection and Immunity, University College London, London, United Kingdom.
Alice C
AC
Len
Division of Infection and Immunity, University College London, London, United Kingdom.
Luke A
LA
Granger
Division of Infection and Immunity, University College London, London, United Kingdom.
Clare
C
Jolly
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D015658:HIV Infections; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014771:Virion; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C498296:VPS26A protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D054299:env Gene Products, Human Immunodeficiency Virus