From negative factor to a critical role in virus pathogenesis: the changing fortunes of Nef

Harris, Mark

doi:10.1099/0022-1317-77-10-2379

Cited by 68 publications

(40 citation statements)

References 90 publications

(29 reference statements)

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“…Nef could directly activate the CD4 ϩ T cells in which it is expressed. It has been shown that Nef expression can activate the proximal TCR machinery (25,51), allowing hyperphosphorylation of effectors such as LAT (23), which has been implicated in T-cell activation (71). On the other hand, the expansion of an activated Tg CD4 ϩ T-cell subset may represent a physiological response to the disease process.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Weng

Priceputu

Chrobák

et al. 2004

J Virol

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The cellular and molecular mechanisms of dysfunction and depletion of CD4 ؉ T lymphocytes over the course of human immunodeficiency virus type 1 (HIV-1) infection are still incompletely understood, but chronic immune activation is thought to play an important role in disease progression. We studied CD4 ؉ T-cell biology in CD4C/HIV transgenic (Tg) mice, in which Nef expression is sufficient to induce a severe AIDS-like disease including a preferential decrease of CD4 ؉ T cells. We show here that Nef-expressing Tg CD4 ؉ T cells exhibit an activated/memory-like phenotype which appears to be independent of antigenic stimulation, as documented in experiments involving breeding with AD10 TcR Tg mice. In addition, in vivo bromodeoxyuridine incorporation showed that a larger proportion of Tg than non-Tg CD4 ؉ T cells entered the S phase. However, in vitro, Tg CD4 ؉ T cells were found to have a very limited capacity to divide in response to stimulation with anti-CD3 and anti-CD28 or in allogeneic mixed leukocyte reactions. Interestingly, despite these observations, the deletion of Tg CD4 ؉ T cells had little impact on the development of other AIDS-like organ phenotypes. Thus, the Nef-induced chronic activation of CD4 ؉ T cells may exhaust the T-cell pool and may contribute to the thymic atrophy and the low number of CD4 ؉ T cells observed in these Tg mice.

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Section: Discussionmentioning

confidence: 99%

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Weng

Priceputu

Chrobák

et al. 2004

J Virol

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“…The study by Milone and Fitzgerald-Bocarsly (35) also suggested that gp120 released from infected cells was acting as a mannose receptor ligand for the induction of IFN-␣. If a gp120-mannose receptor interaction is used by HIV-1 to gain entry into cells, then down-regulation of this receptor would prevent entry of additional virus, a mechanism suggested to be important in HIV-mediated down-regulation of CD4 on T cells to prevent nonproductive infection (37). Third, the mannose receptor is involved in delivery of Ags to intracellular compartments containing MHC class II molecules (4).…”

Section: Figurementioning

confidence: 99%

HIV-1 Tat Represses Transcription from the Mannose Receptor Promoter

Caldwell¹,

Egan

Shepherd

2000

The Journal of Immunology

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The mannose receptor is expressed on mature macrophages and immature dendritic cells, and functions to mediate phagocytosis of pathogens and capture of Ags for delivery to MHC class II-containing intracellular compartments. It has been previously reported that HIV-1-infected macrophages have reduced functions associated with the mannose receptor, including impaired Pneumocystis carinii phagocytosis and mannosylated albumin uptake. Several HIV-1-derived proteins including the Tat protein have been shown to transcriptionally repress host cell genes. The present study was undertaken to define the role of the HIV-1-derived protein Tat in HIV-mediated mannose receptor down-regulation. Cotransfection of the human macrophage cell line U937 with a Tat expression vector and a mannose receptor promoter-luciferase reporter construct resulted in down-regulation of mannose receptor promoter activity. This repression was targeted to the basal promoter. Expression of either one- or two-exon Tat resulted in decreased promoter activity. The addition of the transactivation response element (TAR) sequence enhanced the Tat-mediated repression. Down-regulation was also seen when transfected cells were treated with exogenously added Tat protein. These results are consistent with a mechanism whereby Tat reduces mannose receptor promoter activity by interfering with the host transcriptional initiation machinery, potentially resulting in decreased levels of surface mannose receptor available for Ag or pathogen capture.

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“…Finally, there is evidence that Nef downregulates MHC I in vitro (Collins et al 1998), and that it enhances apoptosis (Xu et al 1997). For reviews, see Geleziunas et al (1996), Harris (1996), Piguet & Trono (1999) and Ratner & Niederman (1995). The extent to which function is reduced in a truncated protein is unclear.…”

Section: Introductionmentioning

confidence: 99%

Intra-host competition between nef–defective escape mutants and wild–type human immunodeficiency virus type 1

Altes

Jansen

2000

Proc. R. Soc. Lond. B

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Various forms of nef genes with deletions at conserved positions along the sequence have been reported to persist in human immunode¢ciency virus type 1 infected patients. We investigate the forces maintaining such variants in the proviral population. The main selection pressures are preservation of function and host immune response. The crippled Nef protein might have fewer epitopes, and as such be less visible to the speci¢c immune response, but it will lose some function. Does a trade-o¡ between avoidance of the immune response and loss of function explain the dynamics of the crippled virus found in the patients ? To answer this question, we formulated a deterministic model of the virus^host interactions. We found that when the crippled protein presents few epitopes and su¡ers little loss of function, the two viral types can coexist. Otherwise, the wild-type comes to prevail. The mutant form might initially dominate, but as the selective pressure by the CD8+ T cells decreases over the course of infection, the advantage for the crippled form of losing epitopes disappears. Hence, we go from a situation of coexistence of wild-type and mutant, to a situation of only full-length nef. The results are discussed in the context of the suggested use of live attenuated vaccines having deletions in nef.

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From negative factor to a critical role in virus pathogenesis: the changing fortunes of Nef

Cited by 68 publications

References 90 publications

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

HIV-1 Tat Represses Transcription from the Mannose Receptor Promoter

Intra-host competition between nef–defective escape mutants and wild–type human immunodeficiency virus type 1

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From negative factor to a critical role in virus pathogenesis: the changing fortunes of Nef

Cited by 68 publications

References 90 publications

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

HIV-1 Tat Represses Transcription from the Mannose Receptor Promoter

Intra-host competition between nef–defective escape mutants and wild–type human immunodeficiency virus type 1

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Product

Resources

About

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease