The frantic play of the concealed HIV envelope cytoplasmic tail

Silva, Eveline Santos da; Mulinge, Martin; Perez-Bercoff, Danielle

doi:10.1186/1742-4690-10-54

Cited by 46 publications

(34 citation statements)

References 272 publications

(437 reference statements)

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“…This model is supported by the finding that the requirement for gp41CT in Env incorporation is cell-type dependent (Akari et al, 2000; Murakami and Freed, 2000b). Numerous cellular factors have been described to interact with gp41CT but their exact functional role is not well understood (reviewed in (Santos da Silva et al, 2013)). Nonetheless, in most of the cases these interactions enhance virus replication.…”

Section: Discussionmentioning

confidence: 99%

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Samal

Vlach

et al. 2017

Structure

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SUMMARY The cytoplasmic tail of gp41 (gp41CT) remains the last HIV-1 domain with an unknown structure. It plays important roles in HIV-1 replication such as mediating envelope (Env) intracellular trafficking and incorporation into assembling virions, mechanisms of which are poorly understood. Herein, we present the solution structure of gp41CT in a micellar environment and characterize its interaction with the membrane. We show that the N-terminal 45 residues are unstructured and not associated with the membrane. However, the C-terminal 105 residues form three membrane-bound amphipathic a-helices with distinctive structural features such as variable degree of membrane penetration, hydrophobic and basic surfaces, clusters of aromatic residues, and a network of cation-p interactions. This work fills a major gap by providing the structure of the last segment of HIV-1 Env, which will provide insights into the mechanisms of Gag-mediated Env incorporation as well as the overall Env mobility and conformation on the virion surface.

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Section: Discussionmentioning

confidence: 99%

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Samal

Vlach

et al. 2017

Structure

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“…The cytoplasmic tail (CT) of gp41 includes three helical regions referred to as lentiviral lytic peptides (LLP) 1–3 [9]. The LLPs have been shown to associate with the cytosolic side of the PM and may influence fusogenicity and immunogenicity of Env [10,11]. The CT also contains motifs involved in signaling, trafficking and endocytosis [12].…”

Section: Combating Hiv-1 and Aidsmentioning

confidence: 99%

The role of matrix in HIV-1 envelope glycoprotein incorporation

Tedbury¹,

Freed²

2014

Trends in Microbiology

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Incorporation of the viral envelope (Env) glycoprotein is a critical requirement for the production of infectious HIV-1 particles. It has long been appreciated that the matrix (MA) domain of the Gag polyprotein and the cytoplasmic tail of Env are central players in the process of Env incorporation, but the precise mechanisms have been elusive. A number of recent developments have thrown light on the contributions of both proteins, prompting a re-evaluation of the role of MA during Env incorporation. The two domains appear to play distinct but complementary roles, with the cytoplasmic tail of Env responsible for directing Env to the site of assembly and the matrix domain accommodating the cytoplasmic tail of Env in the Gag lattice.

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“…These include but are not limited to (i) endocytosis of cell surface Env, (ii) Env trafficking in polarized cells, (iii) Env packaging into viral particles, (iv) controlling the fusogenic potential of Env (1)(2)(3)(4)(5)(6), (v) cell signaling, and (vi) regulating antibody binding (1,7,8) and neutralization sensitivity (8)(9)(10). Many of these functions are associated with specific sequences and/or structural motifs (11)(12)(13)(14)(15). The major defined motifs in the CT include a tyrosine-based endocytic signal near the membranespanning domain, a C-terminal dileucine endocytic motif, a highly immunogenic region (HIR) containing a neutralizing epitope called the Kennedy epitope, a nuclear factor B (NF-B) activation domain (16), three amphipathic alpha helices referred to as lentiviral lytic peptides (LLP), and two inhibitory sequences, is1 and is2, which inhibit Env surface expression (17).…”

mentioning

confidence: 99%

HIV-1 Cell-Free and Cell-to-Cell Infections Are Differentially Regulated by Distinct Determinants in the Env gp41 Cytoplasmic Tail

Durham

Chen

2015

J Virol

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The HIV-1 envelope (Env) glycoprotein mediates viral entry during both cell-free and cell-to-cell infection of CD4 ؉ T cells. The highly conserved long cytoplasmic tail (CT) of Env is required in a cell type-dependent manner for optimal infectivity of cell-free virus. To probe the role of the CT in cell-to-cell infection, we tested a panel of mutations in the CT region that maintain or attenuate cell-free infection to investigate whether the functions of the CT are conserved during cell-free and cell-to-cell infection. The mutations tested included truncations of structural motifs in the gp41 CT and two point mutations in lentiviral lytic peptide 3 (LLP-3) previously described as disrupting the infectivity of cell-free virus. We found that small truncations of 28 to 43 amino acids (aa) or two LLP-3 point mutations, YW_SL and LL_RQ, severely impaired single-round cell-free infectivity 10-fold or more relative to wild-type full-length CT. These mutants showed a modest 2-fold reduction in cell-to-cell infection assays. Conversely, large truncations of 93 to 124 aa severely impaired cell-to-cell infectivity 20-fold or more while resulting in a 50% increase in infectivity of cell-free viral particles when produced in 293T cells. Intermediate truncations of 46 to 90 aa showed profound impairment of both modes of infection. Our results show that the abilities of Env to support cell-free and cell-to-cell infection are genetically distinct. These differences are cell type dependent for large-CT-truncation mutants. Additionally, point mutants in LLP-3 can maintain multiround propagation from cell-to-cell in primary CD4 ؉ T cells. IMPORTANCEThe functions of HIV Env gp41 CT remain poorly understood despite being widely studied in the context of cell-free infection. We have identified domains of the gp41 CT responsible for striking selective deficiencies in either cell-free or cell-to-cell infectivity. These differences may reflect a different intrinsic regulatory influence of the CT on cell-associated versus particle-associated Env or differential interaction with host or viral proteins. Our findings provide novel insight into the key regulatory potential of the gp41 CT in cell-free and cell-to-cell HIV-1 infection, particularly for short-truncation mutants of <43 amino acids or mutants with point mutations in the LLP-3 helical domain of the CT, which are able to propagate via cell-to-cell infection in the absence of infectious cell-free virus production. These mutants may also serve as tools to further define the contributions of cellfree and cell-to-cell infection in vitro and in vivo. Human immunodeficiency virus (HIV-1) is an enveloped retrovirus that can enter permissive target cells through binding of its envelope glycoprotein (Env) to host CD4 and chemokine receptors. Env is a trimer of gp120-gp41 heterodimers and mediates viral attachment, fusion, and entry into CD4 ϩ T cells during both cell-free infection and direct cell-to-cell infection via the virological synapse (VS). The gp41 cytoplasmic tail (CT) of ...

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The frantic play of the concealed HIV envelope cytoplasmic tail

Cited by 46 publications

References 272 publications

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

The role of matrix in HIV-1 envelope glycoprotein incorporation

HIV-1 Cell-Free and Cell-to-Cell Infections Are Differentially Regulated by Distinct Determinants in the Env gp41 Cytoplasmic Tail

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