Retromer regulates HIV-1 envelope glycoprotein trafficking and incorporation into virions.

Elisabetta Groppelli,Clare Jolly,Alice C Len,Luke A Granger,Michael Emerman

doi:10.1371/journal.ppat.1004518

Elisabetta Groppelli, Clare Jolly + Show 3 more

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https://doi.org/10.1371/journal.ppat.1004518

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Journal: PLoS pathogens	Publication Date: Nov 13, 2014
Citations: 106	License type: CC BY 4.0

Affiliation: University College London

Abstract

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.

Highlights

The Human Immunodeficiency Virus type-1 (HIV-1) assembles at the plasma membrane of virus-infected cells from which nascent particles are released by a process of budding
Because envelope glycoprotein (Env) is expressed on the surface of infected cells and is the only viral protein exposed on the virion, it is the major target for neutralizing antibody responses; the mechanism of Env trafficking in HIV-1 infected cells and how it is incorporated into viral particles is poorly understood
The envelope glycoprotein (Env) of HIV is a critical determinant of viral infectivity and is a major target for antiviral immune responses

Summary

Introduction

The Human Immunodeficiency Virus type-1 (HIV-1) assembles at the plasma membrane of virus-infected cells from which nascent particles are released by a process of budding. The envelope glycoprotein (Env) of primate lentiviruses including Human Immunodeficiency Virus type-1 (HIV-1) is a key determinant of viral infectivity, facilitating attachment of virions to the surface of susceptible cells, triggering fusion of the viral and cellular membranes and determining the site of infectious virus assembly at the plasma membrane [1,2,3,4]. Because Env is expressed on the surface of infected cells and is the only viral protein exposed on the virion, it is the major target for neutralizing antibody responses; the mechanism of Env trafficking in HIV-1 infected cells and how it is incorporated into viral particles is poorly understood. Truncation of the cytoplasmic tail of Env has been shown to alter Env intracellular trafficking and to profoundly reduce the infectivity of HIV-1 in many cell types, including CD4 T cells that are the main targets for HIV-1 replication in vivo [7,8]

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