The frantic play of the concealed HIV envelope cytoplasmic tail

Abstract

Lentiviruses have unusually long envelope (Env) cytoplasmic tails, longer than those of other retroviruses. Whereas the Env ectodomain has received much attention, the gp41 cytoplasmic tail (gp41-CT) is one of the least studied parts of the virus. It displays relatively high conservation compared to the rest of Env. It has been long established that the gp41-CT interacts with the Gag precursor protein to ensure Env incorporation into the virion. The gp41-CT contains distinct motifs and domains that mediate both intensive Env intracellular trafficking and interactions with numerous cellular and viral proteins, optimizing viral infectivity. Although they are not fully understood, a multiplicity of interactions between the gp41-CT and cellular factors have been described over the last decade; these interactions illustrate how Env expression and incorporation into virions is a finely tuned process that has evolved to best exploit the host system with minimized genetic information. This review addresses the structure and topology of the gp41-CT of lentiviruses (mainly HIV and SIV), their domains and believed functions. It also considers the cellular and viral proteins that have been described to interact with the gp41-CT, with a particular focus on subtype-related polymorphisms.

Figure 1

Lengths of the cytoplasmic tails of various retroviruses and sequence alignment of different HIV-1 subtypes, clades and types. (A) Comparison of the lengths of the gp41-CT of Human Immunodeficiency Virus type 1 (HIV-1), HIV type 2 (HIV-2), Simian Immunodeficiency Virus (SIV), Feline Immunodeficiency Virus (FIV), Equine Infectious Anemia Virus (EIAV), Maedi-Visna Virus (MVV), Caprine Arthritis Encephalitis Virus (CAEV), Human T-lymphotropic Virus type I (HTLV-1), Human T-lymphotropic Vtype 2 (HTLV-2), Mouse Mammary Tumor Virus (MMTV), Murine Leukemia Virus (MLV) and Gibbon Ape Leukemia Virus (GaLV); conserved YxxФ motifs (where Ф represents a hydrophobic residue) are highlighted. (B) Sequence alignment of the gp41-CT from various lenviviral (HIV and SIV) types and subtypes: HIV-1 subtypes A (92UG037), B (HXB2), C (ETH2220), D (SE365), F1 (93BR020), G (175), H (90CF056), CRF02_AG (93TH065), clade O (ANT70) and clade N (YBF106), HIV-2 (UC2), SIVcpz (Ptt_04CAM155) and SIVsmm (H635). AA positions are aligned against the NL-3 reference used in most studies of the gp41-CT. Lentiviral lytic peptide (LLP) domains, Kennedy epitopes and antibodies directed against them are shown. Conserved YxxФ motifs are highlighted in orange; conserved dileucine motifs, and motifs involved in cell trafficking are highlighted in green.

Figure 2

Schematic representation of the topology of the gp41-CT. A. Conventional model, in which gp41 spans the membrane once and the membrane-spanning domain (MSD) is an α-helix (boxed). B. Alternative model in which the gp41-CT crosses the membrane three times via antiparallel β-sheets (arrows) and the KE is exposed extracellularly. Adapted from Steckbeck et al. PlosOne 2010 [71]. C. LLP-2 is a membrane-traversing peptide or a “carrier” peptide and may interact with the HR1-HR2 6-helix bundle at the moment of fusion. In this conformation, the KE would also traverse the plasma membrane. Adapted from Lu et al. J Biol Chem 2008 [60].

Figure 3

Schematic representation of the interacting partners of the gp41-CT in the cell. The Env precursor gp160 is synthesized in the rough endothelial reticulum (RER), where it is glycosylated and oligomerizes into trimers. Furin cleavage in the Golgi apparatus enables the formation of the gp120-gp41 structure. Once it reaches the plasma membrane (PM), Env is subject to endocytosis, via the Y₇₁₂SPL and L₈₅₅L₈₅₆ motifs interacting with AP-1 and AP-2. Cycling through the trans Golgi network and between endosomes is ensured through interactions with TIP47, via the Y₈₀₂W₈₀₃ diaromatic domain, and with AP-1 via Y₇₁₂SPL. Env is targeted to the PM through Y₇₁₂SPL interaction with AP-1 and AP-3. The p55^Gag precursor is synthesized in the cytoplasm and accumulates at the PM in lipid raft-rich domains. Interaction of the gp41-CT (through LLP-2) with the Matrix protein (MA) ensures Env incorporation into the budding virion. gp41-CT interacts with Nef through L855L856. NF-κB activation through phosphorylation of IκB is mediated by interaction of the Y₇₆₈ with TAK-1. Interference with luman-mediated inhibition of transcription is mediated by LLP-2. Abbreviations: RER: rough endoplasmic reticulum; TGN: trans Golgi network; CaM: calmodulin; LLP: lentiviral lytic peptide; TAK: TFG-β-activating factor; AP: adaptor protein: TIP47: Tail-interacting protein 47 kDa; Ub: ubiquitin ; Phb: Prohibitin.

Figure 4

gp41-CT domains or AA with reported function(s), conservation across subtypes, interacting partners and role of these interactions. Abbreviations: RER: rough endoplasmic reticulum; TGN: trans Golgi network; CaM: calmodulin; LLP: lentiviral lytic peptide; TAK: TFG-β-activating factor; AP: adaptor protein: TIP-47: Tail-interacting protein 47 kDa; Ub: ubiquitin.