The cytoplasmic domain of CD4 plays a critical role during the early stages of HIV infection in T-cells.

Benkirane, Monsef; Jeang, Kuan‐Teh; Devaux, Christian

doi:10.1002/j.1460-2075.1994.tb06893.x

Cited by 70 publications

(79 citation statements)

References 61 publications

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“…It has also been proposed that signals transduced through CD4 may negatively regulate expression of HIV by a mechanism depending on CD4 oligomerization (49). However, controversy exists as to whether these signals are indeed of negative or positive nature (49,50). The Jurkat-T cell lines used in our experiments expressed full-length CD4 molecules, yet we did not observe increased amounts of HIV proteins in infected cells expressing low levels of surface CD4, as compared with high CD4 expressers.…”

Section: Cd4-mediated Inhibition Of Hiv Infectivitymentioning

confidence: 55%

Cell Surface CD4 Interferes with the Infectivity of HIV-1 Particles Released from T Cells

Cortés¹,

Wong‐Staal²,

Lama³

2002

Journal of Biological Chemistry

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The CD4 protein is required for the entry of human immunodeficiency virus (HIV) into target cells. Upon expression of the viral genome, three HIV-1 gene products participate in the removal of the primary viral receptor from the cell surface. To investigate the role of surface-CD4 in HIV replication, we have created a set of Jurkat cell lines which constitutively express surface levels of CD4 comparable to those found in peripheral blood lymphocytes and monocytes. Expression of low levels of CD4 on the surface of producer cells exerted an inhibitory effect on the infectivity of HIV-1 particles, whereas no differences in the amount of cell-free p24 antigen were observed. Higher levels of cell surface CD4 exerted a stronger inhibitory effect on infectivity, and also affected the release of free virus in experiments where the viral genomes were delivered by electrotransfection. The CD4-mediated inhibition of HIV-1 infectivity was not observed in experiments where the vesicular stomatitis virus G protein was used to pseudotype viruses, suggesting that an interaction between CD4 and gp120 is required for interference. In contrast, inhibition of particle release by high levels of cell-surface CD4 was not overcome by pseudotyping HIV-1 with foreign envelope proteins. Protein analysis of viral particles released from HIV-infected Jurkat-T cells revealed a CD4-dependent reduction in the incorporation of gp120. These results demonstrate that physiological levels of cell-surface CD4 interfere with HIV-1 replication in T cells by a mechanism that inhibits envelope incorporation into viral membranes, and therefore provide an explanation for the need to down-modulate the viral receptor in infected cells. Our findings have important implications for the spread of HIV in vivo and suggest that the CD4 down-modulation function may be an alternative target for therapeutic intervention. HIV1 down-modulates its own receptor, the CD4 protein. Removal of CD4 from the surface of infected cells is achieved by the Nef, Vpu, and Env products (1-8). Nef acts early after infection by accelerating the internalization of CD4 and targeting it to late endosomes for degradation (6, 9 -13). Env and Vpu cooperate inside the cell to block the transport of CD4 to the cell surface and redirect this protein to the ubiquitin-proteosome machinery for degradation (1, 14 -16). The Env protein sequesters CD4 in the endoplasmic reticulum by an interaction mediated by the extracellular domains of CD4 and Env (8, 17), whereas Vpu induces the degradation of the HIV receptor by a mechanism which requires an interaction between the cytoplasmic tails of CD4 and Vpu (1,7,18,19). The fact that the combined action of three HIV-1 gene products is required for the nearly complete elimination of CD4 from the cell surface encouraged investigators to examine why HIV has to reduce the cell surface expression of its own receptor. By analogy with other retroviruses, it was first speculated that removal of CD4 from the cell surface would impede superinfection of cells, an eve...

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Section: Cd4-mediated Inhibition Of Hiv Infectivitymentioning

confidence: 55%

Cell Surface CD4 Interferes with the Infectivity of HIV-1 Particles Released from T Cells

Cortés¹,

Wong‐Staal²,

Lama³

2002

Journal of Biological Chemistry

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“…Whether this is because VS formation requires signals to be transduced through CD4 and/or the CKR in response to Env binding, or Env-receptor binding simply mediates sufficiently tight conjugate formation to allow other proteins to interact and elaborate a synapse is unclear. Signal transduction by CD4 (via p56lck) and CKRs is well documented and evidence exists that gp120 engagement of these receptors can initiate signalling cascades (46)(47)(48). CKRs are G-protein coupled receptors and can transduce signals in a G-protein-dependent or -independent manner and this is necessary for cellular polarization and chemotaxis (49).…”

Section: What Directs Vs Formation?mentioning

confidence: 99%

Retroviral Spread by Induction of Virological Synapses

Jolly

Sattentau

2004

Traffic

206

180

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Cells of the immune system communicate via the formation of receptor-containing adhesive junctions termed immunological synapses. Recently, retroviruses have been shown to subvert this process in order to pass directly from infected to uninfected immune cells. Such cell-cell viral dissemination appears to function by triggering existing cellular pathways involved in antigen presentation and T-cell communication. This mode of viral spread has important consequences for both the virus and the host cells in terms of viral pathogenesis and viral resistance to immune and therapeutic intervention. This review summarises the current knowledge concerning virological synapses induced by retroviruses.

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“…For example, binding of Env glycoproteins to chemokine receptors activates calcium flux and chemotaxis in CD4 ϩ T cells (43), and gp120 induces apoptosis in neurons (44), CD4 ϩ T cells (45), and CD8 ϩ T lymphocytes (46). Cross-linking of CD4 with heat-inactivated virus induces signal transduction, resulting in activation of the cellular transcription machinery (47). It has been demonstrated that binding of HIV-1 to its target leads to phosphorylation of PI3K (48).…”

Section: Discussionmentioning

confidence: 99%

HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and CD86 Molecules

Roy

Martin

Giguère

et al. 2005

The Journal of Immunology

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It is well documented that a wide range of host-derived cell surface constituents is inserted within HIV type 1 (HIV-1) and located on the exterior of the virion. Although no virus-associated protein of host origin has been shown to be absolutely required for virus replication, studies have revealed that many of these proteins are functional and can affect several steps of the virus life cycle. In this study, we found that HIV-1 acquires peptide-loaded class II MHC (MHC-II) and the costimulatory CD86 molecules from the host cell. Moreover, we present evidence that virions bearing such peptide-loaded MHC-II and CD86 proteins can lead to activation of the transcription factors NF-κB and NF-AT in an Ag-specific human T cell line. A linear correlation was found between activation of NF-κB and the amount of peptide-loaded MHC-II molecules inserted within HIV-1. Finally, transcription of unintegrated and integrated HIV-1 DNA was promoted upon exposure of peptide-specific human T cells to viruses bearing both peptide-loaded MHC-II and CD86 proteins. These data suggest that HIV-1 can operate as an APC depending on the nature of virus-anchored host cell membrane components. It can be proposed that HIV-1 can manipulate one of its primary targets through the process of incorporation of host-derived proteins.

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The cytoplasmic domain of CD4 plays a critical role during the early stages of HIV infection in T-cells.

Cited by 70 publications

References 61 publications

Cell Surface CD4 Interferes with the Infectivity of HIV-1 Particles Released from T Cells

Cell Surface CD4 Interferes with the Infectivity of HIV-1 Particles Released from T Cells

Retroviral Spread by Induction of Virological Synapses

HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and CD86 Molecules

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