Disease relevance of nef

• Depending on the genes studied, phylogenetic analysis showed that YBF30 branched either with SIVcpz-gab or between SIVcpz-gab and HIV-1 group M. The structural genes and tat, vpr, and nef of YBF30 are approximately equidistant from those of HIV-1 group M and SIVcpz-gab [1].
• Here, we report that HIV infection leads to selective transcription of the nef and tat genes before integration [2].
• We report the complete sequence analysis of the provirus harbored in a long-term nonprogressor (patient SG1) 20 years after the first infection with a human immunodeficiency virus type 1 strain lacking nef [3].
• Notably, nef alleles from AIDS patients were more effective in preventing superinfection than those derived from a nonprogressor of HIV-1 infection [4].
• To circumvent these issues, a novel chimeric polyprotein vaccine candidate (Retanef), comprising genetically modified and re-assorted rev, tat, and nef open reading frames of simian immunodeficiency virus (SIV), was constructed and optimized for its expression in mammalian cells [5].

Psychiatry related information on nef

• We have cloned 97 nef genes and characterized 10 Nef proteins from autopsy brain and lymphoid tissues from 2 patients with AIDS and HIV-1-associated dementia [6].
• The results suggest that although the evolution of other loci is inversely correlated to the onset and rate of clinical disease, differential evolution of nef is related neither to drug abuse nor to rapid progression within the first 20 weeks of infection [7].
• Unlike our earlier studies of tat and env, nef evolution was not affected by morphine abuse or by rapid disease progression [7].
• We report here that the addition of MG132 or lactacystin, each a specific inhibitor of cellular proteasome activity, preferentially enhances cellular permissiveness to infection by Nef-defective versus wild-type HIV-1 [8].
• Anomalies in Nef expression within the central nervous system of HIV-1 positive individuals/AIDS patients with or without AIDS dementia complex [9].

High impact information on nef

• Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation [10].
• In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death [10].
• (2006) show that the Nef protein from nonpathogenic strains of simian immunodeficiency virus (SIV) induces the downregulation of host T cell receptor/CD3, whereas Nef from human immunodeficiency virus (HIV-1) does not [11].
• This loss of function in the Nef of HIV-1 may partly explain the pathogenicity of this virus [11].
• Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system [10].

Chemical compound and disease context of nef

• HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane [12].
• A conserved acidic leucine-based sequence (E(160)xxxLL) within human immunodeficiency virus type 1 (HIV-1) Nef binds to the cellular adaptor protein (AP) complexes, which mediate protein sorting into endosomal vesicles [13].
• HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor [14].
• Since human immunodeficiency virus (HIV) nef has been suggested to exert regulatory effects on HIV long terminal repeat (LTR) activity, we transiently transfected HIV LTR chloramphenicol acetyltransferase or luciferase expression vectors into a human astrocytoma clone (U-373nef) that constitutively expresses the HIV nef gene [15].
• We conclude that skin components show expression of epitopes recognized by antibodies to HIV-1 tat, rev, and nef; this expression is more extensive in atopic dermatitis than in normal skin, and can be further increased after epicutaneous allergen patch testing.(ABSTRACT TRUNCATED AT 250 WORDS)[16]

Biological context of nef

• One transgenic line was established from the nef founder mouse with the mildest phenotype [17].
• Moreover, nef induced saturation density and loss of contact inhibition [18].
• Functional analysis of predominant nef genes by both a cell surface CD4 downregulation and a viral infectivity complementation assay showed wild-type function [19].
• We believe that, when down-regulation of the class 1 major histocompatibility complex molecules is inhibited by the lack of nef function, the cells containing Env-defective molecules evade cytotoxic T lymphocyte killing and accumulate progressively [3].
• The Delta3 candidate vaccine strain of HIV-1 contains deletions in the viral long terminal repeat (LTR) promoter and the vpr and nef genes [20].

Anatomical context of nef

• Here, we performed a structure-function analysis of the Nef protein by comparing the effect on T-cell development of different nef alleles, either wild type or defective for selected functions, expressed by human thymocytes [21].
• We have previously shown that an env and nef deleted HIV-1 vector (HIV-1 delta EN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34(+) precursors of DCs [22].
• The HIV-1 gene nef is important for progression toward AIDS and cellular depletion of the infected thymus [21].
• These findings indicate that vpr and nef each can induce podocyte injury with a prominent synergistic interaction [17].
• The relevance of the accessory vpr, vpu, and nef genes for human immunodeficiency virus type 1 (HIV-1) replication in human lymphoid tissue (HLT), the major site of viral replication in vivo, is largely unknown [23].

Associations of nef with chemical compounds

• Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription [12].
• This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE [24].
• These effects depend on the leucine-based motif of Nef, which is required for the membrane stabilization of AP-1 and AP-3 complexes [25].
• These complexes remained with Nef on juxtanuclear membranes despite the treatment of cells with brefeldin A, which induced the release of ADP-ribosylation factor 1 (ARF1) from these membranes to the cytosol [26].
• To further elucidate how Nef disrupts MHC-I trafficking in T cells, we examined the role of protein domains that are required for this function (N-terminal alpha helix, polyproline, acidic, and oligomerization domains) [27].

Physical interactions of nef

• Using transient transfection assay, co-immunoprecipitation and pull-down analysis, we demonstrate in this report that the HIV-1 Nef protein physically interacts with Tat, the principal transactivating protein of HIV-1 [28].

Regulatory relationships of nef

• The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function [12].
• Consistent with these quantitative differences, Nef inhibited superinfection more efficiently than Vpu and Env [4].
• Similarly, cells transduced with LrevSN were able to rescue a rev- HIV-1 provirus, indicating the presence of a functional Rev. We also used LnefSN to obtain clones of cells expressing Nef [29].
• ENF resistance mutations, selected in vitro or in vivo, were introduced into the env gene of HIV-1(NL4-3) by site-directed mutagenesis and expressed in HIV-1 recombinants carrying sequence tags in nef [30].

Other interactions of nef

• In support of this possibility, mutations at rev 3' splice site A4b AG dinucleotide dramatically increased splicing of the env/nef 3' splice site A5 [31].
• For testing effects of simultaneous expression of vpr and nef, these two lines were mated [17].
• Vif, Vpu and Nef as a fusion protein with proteolytic cleavage sites (VVN-P) is able to induce a significant level of cellular immune responses [32].
• RESULTS: DNA vaccine construct (pVVN-P) expressing Vif, Vpu and Nef was processed and the fusion protein was cleaved appropriately [32].
• VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n=10) or study vaccine at 2 mg (n=5), 4 mg (n=20), or 8 mg (n=15) by needle-free intramuscular injection [33].

Analytical, diagnostic and therapeutic context of nef

• By comparing nef-competent and nef-deleted HIV-1 strains in an in vitro coculture system, we demonstrate that the presence of this viral accessory gene leads to impairment of the ability of HIV-1-specific CTL clones to suppress viral replication [34].
• DNA vaccination in mice using HIV-1 nef, rev and tat genes in self-replicating pBN-vector [35].
• Previous work from our laboratory has shown that Nef also promotes proliferation of myeloid cells through a signal transducer and activator of transcription 3-dependent pathway [36].
• We have used combined immunocytochemistry and in situ hybridization to study firstly, the order of expression of regulatory HIV-1 proteins Nef, Rev and Tat in relation to non-spliced and spliced mRNA expression and secondly, the subcellular localization of these proteins in acutely and chronically infected human T-cell lines [37].
• Persistent infection of MT-4 cells by human immunodeficiency virus type 1 becomes increasingly likely with in vitro serial passage of wild-type but not nef mutant virus [38].

References