The Nef protein of primate lentiviruses

Piguet, Vincent; Trono, Didier

doi:10.1002/(sici)1099-1654(199904/06)9:2<111::aid-rmv245>3.0.co;2-p

Cited by 75 publications

(31 citation statements)

References 93 publications

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“…Nef is a 27-to 34-kDa myristoylated protein, which is unique and highly conserved among primate lentiviruses [39]. It is one of several early proteins made shortly after infection and plays an important role in the maintenance of infection and the progression to AIDS.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor

Vigerust

Egan

Shepherd

2005

Journal of Leukocyte Biology

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Human immunodeficiency virus (HIV) has derived a variety of means to evade the host immune response. HIV-derived proteins, including Tat, Nef, and Env, have all been reported to decrease expression of host molecules such as CD4 and major histocompatibility complex I, which would assist in limiting viral replication. The mannose receptor (MR) on the surface of macrophages and dendritic cells (DC) has been proposed to function as an effective antigen-capture molecule, as well as a receptor for entering pathogens such as Mycobacterium tuberculosis and Pneumocystis carinii. Regulation of this receptor would therefore benefit HIV in removing an additional arm of the innate immune system. Previous work has shown that MR function is reduced in alveolar macrophages from HIV-infected patients and that surface MR levels are decreased by the HIV-derived protein Nef in DC. In addition, several laboratories have shown that CD4 is removed from the surface of T cells in a manner that might be applicable to decreased MR surface expression in macrophages. In the current study, we have investigated the role of Nef in removing MR from the cell surface. We have used a human macrophage cell line stably expressing the MR as well as human epithelial cells transiently expressing CD4 and a unique CD4/MR chimeric molecule constructed from the extracellular and transmembrane domains of CD4 and the cytoplasmic tail portion of the MR. We show that the MR is reduced on the cell surface by approximately 50% in the presence of Nef and that the MR cytoplasmic tail can confer susceptibility to Nef in the CD4/MR chimera. These data suggest that the MR is a potential intracellular target of Nef and that this regulation may represent a mechanism to further cripple the host innate immune system.

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Section: Introductionmentioning

confidence: 99%

HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor

Vigerust

Egan

Shepherd

2005

Journal of Leukocyte Biology

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“…As important as Tat and Rev are to productive viral infection, the Nef protein is to viral pathogenesis, being required for high-titer virus replication in vivo, and critical for the development of AIDS (Kestler et al, 1991). Nef modulates the host immune response to HIV infection by downregulating both CD4 and MHC class I molecules on the surface of infected cells (Collins et al, 1998;Piguet and Trono, 1999), thereby diminishing host control of viral infection. Thus, immune inhibition of Nef functions could also enhance protection against viral infection.…”

Section: Introductionmentioning

confidence: 99%

Potent, Persistent Cellular Immune Responses Elicited by Sequential Immunization of Rhesus Macaques with Ad5 Host Range Mutant Recombinants Encoding SIV Rev and SIV Nef

Patterson

Malkevitch²,

Zhao³

et al. 2002

DNA and Cell Biology

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Vaccines incorporating multiple HIV components should elicit broad immunity and protection against a spectrum of HIV strains. Early regulatory and accessory gene products are attractive candidates for such vaccines. Here, immunogenicity studies on SIV Rev and Nef expressed in replication competent Adenovirus type 5 host range mutant vectors (Ad5hr) are summarized. Interferon-gamma (IFN-gamma)-secreting cells in response to Env and Rev peptides were enumerated by ELISPOT after two sequential immunizations of 55 macaques with Ad5hr-SIVenv/rev. Responses to SIV Nef were assessed in 16 macaques also immunized with Ad5hr-SIVnef. Potent cellular immunity to both Rev and Nef was induced following the second Ad-recombinant immunization and persisted for at least 30 weeks. Persistent cellular immunity to SIV Env was also seen, with a mean of 700 IFN-gamma-secreting cells per million PBMC. Rev and Env responses were positively correlated. While greater responses to early gene products occur in natural infection, as immunogens Rev and Nef elicited the same number of IFN-gamma secreting cells as Env, after adjusting for differences in protein size. The same percentage of macaques also responded to Rev, Nef, and Env: 59, 63, and 64%, respectively. Overall, Ad5hrSIVenv/rev and -SIVnef were highly effective immunogens. Their contribution to protective efficacy will be addressed in future studies.

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“…14,15 This protein would lack the myristoylation signal and would thus, because of unsuccessful myristoylation, most probably not fold correctly or be directed to the membrane. 16 All isolates with the exception of TV005, TV006, TV012, and TV013 as well as reference strain 96BW12-10 from Botswana have conserved GGXXS motifs in their myristoylation signals. It has been described that GSXXS mutations are possibly associated with slow disease progression 17 and that deletion or substitution of the glycine residues, to which the myristylic acid is linked, prohibits myristoylation.…”

mentioning

confidence: 99%

Characterization of the South African HIV Type 1 Subtype C Complete 5′ Long Terminal Repeat,nef,and Regulatory Genes

Scriba

Villiers

Treurnicht

et al. 2002

AIDS Research and Human Retroviruses

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Human immunodeficiency virus type 1 (HIV-1) subtype C has become the major etiological agent in the global and especially African epidemic. To gain better understanding of the genetic diversity and rapid transmission of HIV-1 subtype C, we have characterized the complete 5' long terminal repeat (LTR) region along with the regulatory genes tat and rev as well as the accessory gene nef of 14 South African HIV-1 subtype C isolates. Phylogenetic analysis revealed a subtype C 5' LTR cluster, as well as subclustering of our nef sequences with various subtype C strains separate from the India and China subclusters. At least 3 NF-kappaB sites were present in the 5' LTR of most isolates and 13 isolates had the subtype C-specific Rev truncation. Some length variation in exon 2 and the absence of a critical cysteine were found in Tat. Residue variation in the myristoylation signal and motifs involved in CD4 and MHC-I downregulation was recorded in our nef gene sequences.

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The Nef protein of primate lentiviruses

Cited by 75 publications

References 93 publications

HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor

HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor

Potent, Persistent Cellular Immune Responses Elicited by Sequential Immunization of Rhesus Macaques with Ad5 Host Range Mutant Recombinants Encoding SIV Rev and SIV Nef

Characterization of the South African HIV Type 1 Subtype C Complete 5′ Long Terminal Repeat,nef,and Regulatory Genes

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