Nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1

  title={Nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1},
  author={Michael Schindler and Jan M{\"u}nch and Olaf Kutsch and Hui Li and Mario L. Santiago and Frédéric Bibollet-Ruche and Michaela M{\"u}ller-Trutwin and Francis J. Novembre and Martine Peeters and Val{\'e}rie Courgnaud and Elizabeth Bailes and Pierre Roques and Donald L Sodora and Guido Silvestri and Paul M. Sharp and Beatrice H. Hahn and Frank Kirchhoff},

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It is reported that engineering HIV-1 for Nef-mediated down-regulation of CD3 reduces Env-dependent HIV- 1 infectivity, resulting in less efficient cell-to-cell spread and replication and loss of an otherwise conserved function of Nef has a positive effect on HIV-2 replication.

Nef-Mediated Enhancement of Virion Infectivity and Stimulation of Viral Replication Are Fundamental Properties of Primate Lentiviruses

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Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms

The results indicate that primate lentiviral Nef proteins impair development of thymocyte precursors into T cells in multiple ways and is likely to be relevant for peripheral T-cell depletion in poorly adapted primate Lentiviral infections.

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

A striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals.

Role of Nef in primate lentiviral immunopathogenesis

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Lentiviral Nef Proteins Manipulate T Cells in a Subset-Specific Manner

The results indicate that Nef predominantly modulates surface receptors on CD4+ T cell subsets that are not already fully permissive for viral replication, and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of central memory CD4- T cells, which are critical for the maintenance of a functional immune system.

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

It is shown that primate lentiviruses follow distinct evolutionary paths to modulate NF-κB-dependent expression of viral and antiviral genes, and those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-σκB activation.

Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation.

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The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses.

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HIV and SIV Nef modulate signal transduction and protein sorting in T cells.

The progressive loss of CD4+ T lymphocytes, the hallmark of AIDSinfection, reflects the host's inability to regenerate thesecells as immunodeficiency viruses disrupt the normalfunction of the lymphoid organs.

The Nef protein of HIV-1 associates with rafts and primes T cells for activation.

It is demonstrated that Nef increases IL-2 secretion from T cells stimulated via CD3 or CD28, which requires the conservation of the Nef myristoylation signal and SH3-binding proline-based motif to prime T cells for activation.

HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes

It is found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed and Nef protected infected cells by reducing the epitope density on their surface.

Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract

It is demonstrated that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4- T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy.

Hyper-responsiveness to Stimulation of Human Immunodeficiency Virus-infected CD4+ T Cells Requires Nef and Tat Virus Gene Products and Results from Higher NFAT, NF-κB, and AP-1 Induction*

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Nef Proteins from Simian Immunodeficiency Virus-Infected Chimpanzees Interact with p21-Activated Kinase 2 and Modulate Cell Surface Expression of Various Human Receptors

The finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.

Nef Proteins from Diverse Groups of Primate Lentiviruses Downmodulate CXCR4 To Inhibit Migration to the Chemokine Stromal Derived Factor 1

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The data demonstrate that over one-half of all memory CD4+ T cells in SIV-infected macaques are destroyed directly by viral infection during the acute phase—an insult that certainly heralds subsequent immunodeficiency.

In vivo analysis of Nef function.

The different model systems that have been used to study Nef function in vivo and the information that they have provided regarding the best characterized in vitro Nef activities are reviewed.