Reevaluation of the Requirement for TIP47 in Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Incorporation

Checkley, Mary Ann; Luttge, Benjamin G.; Mercredi, Peter Y.; Kyere, Sampson; Donlan, Justin; Murakami, Tsutomu; Summers, Michael F.; Simon, Chantal; Freed, Eric O.

doi:10.1128/jvi.03299-12

Cited by 32 publications

(22 citation statements)

References 52 publications

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“…A second highly conserved YW motif lies just C-terminal at position 802 and was previously implicated in Env incorporation and in linking Env to TIP47 (19). However, the connection between Env and TIP47 has not been supported in other studies (20).…”

Section: Discussionmentioning

confidence: 55%

A tyrosine-based motif in the HIV-1 envelope glycoprotein tail mediates cell-type– and Rab11-FIP1C–dependent incorporation into virions

Chu

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lentiviruses such as HIV-1 encode envelope glycoproteins (Env) with long cytoplasmic tails (CTs) that include motifs mediating interactions with host-cell-trafficking factors. We demonstrated recently that Rab11-family interacting protein 1C (FIP1C) is required for CTdependent incorporation of Env into HIV-1 particles. Here, we used viruses bearing targeted substitutions within CT to map the FIP1C-dependent incorporation of Env. We identified YW 795 as a critical motif mediating cell-type-dependent Env incorporation. Disruption of YW 795 reproduced the cell-type-dependent particle incorporation of Env that had previously been observed with large truncations of CT. A revertant virus bearing a single amino acid change near the C terminus of CT restored wild-type levels of Env incorporation, GagEnv colocalization on the plasma membrane, and viral replication. These findings highlight the importance of YW 795 in the cell-typedependent incorporation of Env and support a model of HIV assembly in which FIP1C/RCP mediates Env trafficking to the particle assembly site.HIV assembly | HIV envelope | pseudotyping | FIP1C | Rab coupling protein L entiviruses such as HIV encode envelope glycoproteins (Envs) with long cytoplasmic tails (CTs) of 150 amino acids or more, whereas avian and murine retroviruses generally encode CTs of 20-30 residues. The reasons for this difference are not entirely clear, but may be attributable to interactions with host-trafficking pathways that define the specificity of Env incorporation into viral particles. A large number of tyrosine-and dileucine-based motifs are present in the HIV-1 Env CT, some of which have been shown to interact with factors involved in vesicular trafficking. The membrane-proximal Yxxϕ motif (Y 712 ) has been well studied and serves as a docking site for the μ-subunit of the clathrin adaptor AP-2 (1, 2). Disruption of this motif enhances cell-surface Env concentration, yet somewhat paradoxically reduces Env incorporation into particles and particle infectivity (3-6). Disruption of YW 802 has also been shown to reduce Env incorporation and infectivity (5, 7). The C-terminal dileucine LL 855 motif interacts with the AP-1 (8) or AP-2 (9) clathrin adaptor proteins and plays a role in endocytosis and in determining the cell-surface levels of Env. We recently performed a systematic mutagenesis of tyrosine-and dileucine-based motifs in the Env CT that confirmed the importance of Y 712 on cellsurface levels of Env (3). This study also illuminated an important region of the CT-spanning residues 795-803, in which disruption of YW or LL motifs had dramatic effects on viral replication.In an important advance to our understanding of the role of the Env CT, Murakami and Freed demonstrated that the incorporation of Env into viral particles was cell-type-dependent and that this incorporation in most T-cell lines and macrophages requires an intact long cytoplasmic tail (10). They demonstrated that Env incorporation in 293T cells did not require the long CT, nor was the CT absolutely requi...

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Section: Discussionmentioning

confidence: 55%

A tyrosine-based motif in the HIV-1 envelope glycoprotein tail mediates cell-type– and Rab11-FIP1C–dependent incorporation into virions

Chu

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…While the presence of Env is necessary for cell-free infection, the structure of the tail or its ability to recruit a trans-acting factor(s) may influence infection levels of cell-free but not cell-to-cell HIV-1. A recent study by Checkley et al found that knockdown of TIP47 in Jurkat cells did not alter envelope incorporation, virus production, or infectivity of cell-free HIV particles (65), indicating that TIP47 may not be critical to the originally described phenotype of reduced Env incorporation and cell-free infectivity. While the role of TIP47 as a trans-acting factor involved in Env packaging has been called into question, our results are consistent with studies describing these LLP-3 amino acid residues as important for infection (18)(19)(20).…”

Section: Discussionmentioning

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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“…This myristate and a stretch of highly basic amino acids at the N-terminal end of MA play important roles in Gag targeting to the plasma membrane. In addition, interactions of MA with the cytoplasmic tail of gp41, directly or indirectly through a yet to be determined host factor (81), are critical for efficient incorporation of functional Env into budding virus particles (32,33,71,72). Furthermore, recent studies have also suggested that Env trimers on the HIV-1 virion are reorganized to cluster prior to engagement with CD4, a reorganization process triggered by internal core maturation (82).…”

Section: Discussionmentioning

confidence: 99%

Virus Particle Release from Glycosphingolipid-Enriched Microdomains Is Essential for Dendritic Cell-Mediated Capture and Transfer of HIV-1 and Henipavirus

Akiyama

Miller

Patel

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) exploits dendritic cells (DCs) to promote its transmission to T cells. We recently lentivirus particles by MDCs were severely attenuated upon depletion of GSLs from virus particles. These results suggest that GSL incorporation into virions is critical for the interaction of diverse enveloped RNA viruses with DCs and that the GSL-CD169 recognition nexus might be a conserved viral mechanism of parasitization of DC functions for systemic virus dissemination. IMPORTANCEDendritic cells (DCs) can capture HIV-1 particles and transfer captured virus particles to T cells without establishing productive infection in DCs, a mechanism of HIV-1 trans infection. We have recently identified CD169-mediated recognition of GM3, a host-derived glycosphingolipid (GSL) incorporated into the virus particle membrane, as the receptor and ligand for the DC-HIV trans infection pathway. In this study, we have identified the matrix (MA) domain of Gag to be the viral determinant that governs incorporation of GM3 into HIV-1 particles, a previously unappreciated function of the HIV-1 MA. In addition, we demonstrate that the GSL-CD169-dependent trans infection pathway is also utilized as a dissemination mechanism by henipaviruses. GSL incorporation in henipaviruses was also dependent on the viral capsid (M) protein-directed assembly and budding from GSL-enriched lipid microdomains. These findings provide evidence of a conserved mechanism of retrovirus and henipavirus parasitization of cell-to-cell recognition pathways for systemic virus dissemination.

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Reevaluation of the Requirement for TIP47 in Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Incorporation

Cited by 32 publications

References 52 publications

A tyrosine-based motif in the HIV-1 envelope glycoprotein tail mediates cell-type– and Rab11-FIP1C–dependent incorporation into virions

A tyrosine-based motif in the HIV-1 envelope glycoprotein tail mediates cell-type– and Rab11-FIP1C–dependent incorporation into virions

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

Virus Particle Release from Glycosphingolipid-Enriched Microdomains Is Essential for Dendritic Cell-Mediated Capture and Transfer of HIV-1 and Henipavirus

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