HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

Haller, Claudia; Müller, Birthe; Fritz, Joëlle V.; Lamas-Murua, Miguel; Stolp, Bettina; Pujol, François M.; Keppler, Oliver T.; Fackler, Oliver T.

doi:10.1128/jvi.02333-14

Cited by 76 publications

(92 citation statements)

References 115 publications

(135 reference statements)

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“…1C and D), Nef also contributes to the phenomenon, specifically by downregulating the levels of tetraspanins at the plasma membrane. This finding parallels the results shown in a report by Haller and colleagues (45), which reveals a role in tetraspanin downregulation for Nef, as well as for Vpu.…”

Section: Resultssupporting

confidence: 92%

“…Figure 1F shows that these mutants were still able to downregulate CD81, indicating that Vpu-mediated CD81 downregulation is independent of the 52/56 serine motif or the transmembrane domain of Vpu. This further confirms that this effect is not a by-product of either CD4 or BST-2/tetherin downregulation but, rather, constitutes a previously unrecognized function of Vpu, as was also revealed in the report by Haller and colleagues (45).…”

Section: Resultssupporting

confidence: 88%

“…This intriguing finding falls in line with a major role of Nef in the retrieval of proteins directly from the surfaces of infected cells, as opposed to Vpu, which intercepts surface proteins during their trafficking to the plasma membrane (56). Notably, work by the Fackler group (presented in the report by Haller et al [45]), who performed a comprehensive screen of host cell receptors downregulated by Nef and Vpu, yielded the same information regarding these two accessory proteins.…”

Section: Discussionmentioning

confidence: 62%

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Vpu Is the Main Determinant for Tetraspanin Downregulation in HIV-1-Infected Cells

Lambelé

Koppensteiner

Symeonides

et al. 2015

J Virol

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Tetraspanins constitute a family of cellular proteins that organize various membrane-based processes. Several members of this family, including CD81, are actively recruited by HIV-1 Gag to viral assembly and release sites. Despite their enrichment at viral exit sites, the overall levels of tetraspanins are decreased in HIV-1-infected cells. Here, we identify Vpu as the main viral determinant for tetraspanin downregulation. We also show that reduction of CD81 levels by Vpu is not a by-product of CD4 or BST-2/ tetherin elimination from the surfaces of infected cells and likely occurs through an interaction between Vpu and CD81. Finally, we document that Vpu-mediated downregulation of CD81 from the surfaces of infected T cells can contribute to preserving the infectiousness of viral particles, thus revealing a novel Vpu function that promotes virus propagation by modulating the host cell environment. IMPORTANCEThe HIV-1 accessory protein Vpu has previously been shown to downregulate various host cell factors, thus helping the virus to overcome restriction barriers, evade immune attack, and maintain the infectivity of viral particles. Our study identifies tetraspanins as an additional group of host factors whose expression at the surfaces of infected cells is lowered by Vpu. While the downregulation of these integral membrane proteins, including CD81 and CD82, likely affects more than one function of HIV-1-infected cells, we document that Vpu-mediated lowering of CD81 levels in viral particles can be critical to maintaining their infectiousness. Tetraspanins are integral membrane proteins that span the lipid bilayer four times. The 33 members (in humans) of this protein family, by homo-and hetero-oligomerizing and by laterally interacting with other proteins and with lipids, form a web that serves as the basis for their involvement in the organization of membranes. When triggered by intra-or extracellular cues, socalled tetraspanin-enriched microdomains (TEMs) can form, and these platforms then support or modulate various membranebased processes, including cell adhesion, membrane fusion, signaling, and protein sorting. Consequently, tetraspanins play roles in a wide range of biological activities, such as fertilization, muscle formation and repair, generation of synaptic contacts at neuromuscular junctions, maintenance of skin integrity, and induction of immune responses (1-4). They are also implicated in pathologies, including cancer (e.g., metastasis [5]) and inherited disorders (6), as well as in the propagation and pathogenesis of numerous infectious agents (parasites, bacteria, and viruses) (7-11).While one member of the tetraspanin family (CD63) was shown more than 2 decades ago to be specifically acquired by HIV-1 particles released from infected cells (12)(13)(14), only during the past decade has work by several groups documented that tetraspanins play roles during different stages of the viral replication cycle (for recent reviews, see references 9 and 15). The tetraspanins CD9, CD53, CD63, CD81, CD...

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 62%

See 1 more Smart Citation

Vpu Is the Main Determinant for Tetraspanin Downregulation in HIV-1-Infected Cells

Lambelé

Koppensteiner

Symeonides

et al. 2015

J Virol

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“…Although a direct interaction between HIV-1 Vpu and Nef is yet to be explored, Vpu and Nef share common activities to downregulate various host proteins (e.g., tetherin, CD4, and CD62L) (341,454,455). It has been shown that human tetherin (also termed BST2) interacts with Vpu (456)(457)(458)(459)(460)(461)(462)(463) and Nef (464).…”

Section: Vpu-tetherin/cd4-nef Associationmentioning

confidence: 99%

“…HIV-1 Nef also mediates the postendocytic targeting of internalized CD4 from the endosomes to the multivesicular body pathway, leading to the eventual degradation of CD4 in lysosomes (477). In addition to CD4, HIV-1 Vpu and Nef downregulate a broad spectrum of more than 32 cell surface receptors (454). Significant downregulation has been observed in the tetraspanin protein family harboring various cellular proteins (e.g., CD9, CD53, CD63, CD81, and CD82) that take part in membrane-based processes (454,478).…”

Section: Vpu-tetherin/cd4-nef Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Downregulation of CCR5 on brain perivascular macrophages in simian immunodeficiency virus‐infected rhesus macaques

et al. 2023

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BackgroundC‐C chemokine receptor 5 (CCR5) is a major coreceptor for Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) cell entry; however, its role in brain pathogenesis is largely understudied. Thus, we sought to examine cell type‐specific protein expression of CCR5 during SIV infection of the brain.MethodsWe examined occipital cortical tissue from uninfected rhesus macaques and SIV‐infected animals with or without encephalitis using immunohistochemistry and immunofluorescence microscopy to determine the number and distribution of CCR5‐positive cells.ResultsAn increase in the number of CCR5+ cells in the brain of SIV‐infected animals with encephalitis was accounted for by increased CD3+CD8+ cells expressing CCR5, but not by increased CCR5+ microglia or perivascular macrophages (PVMs), and a concurrent decrease in the percentage of CCR5+ PVMs was observed. Levels of CCR5 and SIV Gag p28 protein expression were examined on a per‐cell basis, and a significant, negative relationship was established indicating decreased CCR5 expression in productively infected cells. While investigating the endocytosis‐mediated CCR5 internalization as a mechanism for CCR5 downregulation, we found that phospho‐ERK1/2, an indicator of clathrin‐mediated endocytosis, was colocalized with infected PVMs and that macrophages from infected animals showed significantly increased expression of clathrin heavy chain 1.ConclusionsThese findings show a shift in CCR5‐positive cell types in the brain during SIV pathogenesis with an increase in the number of CCR5+ CD8 T cells, and downregulated CCR5 expression on infected PVMs, likely through ERK1/2‐driven, clathrin‐mediated endocytosis.

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HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

Cited by 76 publications

References 115 publications

Vpu Is the Main Determinant for Tetraspanin Downregulation in HIV-1-Infected Cells

Vpu Is the Main Determinant for Tetraspanin Downregulation in HIV-1-Infected Cells

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Downregulation of CCR5 on brain perivascular macrophages in simian immunodeficiency virus‐infected rhesus macaques

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