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PMID: 11024110 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Disrupting surfaces of nef required for downregulation of CD4 and for enhancement of virion infectivity attenuates simian immunodeficiency virus replication in vivo.

Journal of virology ·Vol. 74 ·No. 21 ·2000-11-00 ·Pages 9836-44

Iafrate AJ, Carl S, Bronson S, Stahl-Hennig C, Swigut T, Skowronski J, Kirchhoff F

Abstract

The multifunctional simian and human immunodeficiency virus (SIV and HIV) Nef proteins are important for virulence. We studied the importance of selected Nef functions using an SIV Nef with mutations in two regions that are required for CD4 downregulation. This Nef mutant is defective for downregulating CD4 and, in addition, for enhancing SIV infectivity and induction of SIV replication from infected quiescent peripheral blood mononuclear cells, but not for other known functions, including downregulation of class I major histocompatibility complex (MHC) cell surface expression. Replication of SIV containing this Nef variant in rhesus monkeys was attenuated early during infection. Subsequent increases in viral load coincided with selection of reversions and second-site compensatory changes in Nef. Our results indicate that the surfaces of Nef that mediate CD4 downregulation and the enhancement of virion infectivity are critical for SIV replication in vivo. Furthermore, these findings indicate that class I MHC downregulation by Nef is not sufficient for SIV virulence early in infection.

MeSH Terms
Amino Acid Substitution Animals CD4 Antigens/metabolism Down-Regulation Gene Products, nef/chemistry,genetics,metabolism Macaca mulatta Mutation Sequence Analysis, DNA Simian Acquired Immunodeficiency Syndrome/physiopathology,virology Simian Immunodeficiency Virus/pathogenicity,physiology Viral Load Virion/pathogenicity Virulence Virus Replication
Chemicals
CD4 Antigens Gene Products, nef
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Iafrate A J
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Carl S
Bronson S
Stahl-Hennig C
Swigut T
Skowronski J
Kirchhoff F
References (48)
48 references, click to expand
  1. High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection.
    J Virol. 1996 Nov;70(11):7752-64 PMID: 8892896
  2. The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages.
    J Exp Med. 1994 Jan 1;179(1):101-13 PMID: 8270859
  3. Construction, replication, and immunogenic properties of a simian immunodeficiency virus expressing interleukin-2.
    J Virol. 1997 Mar;71(3):2225-32 PMID: 9032357
  4. Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling.
    EMBO J. 1997 Feb 17;16(4):673-84 PMID: 9049297
  5. A role for natural simian immunodeficiency virus and human immunodeficiency virus type 1 nef alleles in lymphocyte activation.
    J Virol. 1997 Aug;71(8):6094-9 PMID: 9223503
  6. Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques.
    Nat Med. 1997 Aug;3(8):860-5 PMID: 9256276
  7. Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation.
    EMBO J. 1997 Dec 1;16(23):6964-76 PMID: 9384576
  8. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques.
    J Virol. 1998 Jan;72(1):164-9 PMID: 9420212
  9. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes.
    Nature. 1998 Jan 22;391(6665):397-401 PMID: 9450757
  10. Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes.
    EMBO J. 1998 May 1;17(9):2472-81 PMID: 9564030
  11. The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes.
    EMBO J. 1998 May 15;17(10):2777-89 PMID: 9582271
  12. Sequences just upstream of the simian immunodeficiency virus core enhancer allow efficient replication in the absence of NF-kappaB and Sp1 binding elements.
    J Virol. 1998 Jul;72(7):5589-98 PMID: 9621017
  13. Role of the SH3-ligand domain of simian immunodeficiency virus Nef in interaction with Nef-associated kinase and simian AIDS in rhesus macaques.
    J Virol. 1998 Jul;72(7):5820-30 PMID: 9621042
  14. HIV-1 auxiliary proteins: making connections in a dying cell.
    Cell. 1998 May 29;93(5):685-92 PMID: 9630214
  15. HIV-1 regulatory/accessory genes: keys to unraveling viral and host cell biology.
    Science. 1998 Jun 19;280(5371):1880-4 PMID: 9632380
  16. Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity.
    Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11229-34 PMID: 9736718
  17. Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice.
    Cell. 1998 Oct 16;95(2):163-75 PMID: 9790524
  18. Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation.
    J Gen Virol. 1998 Nov;79 ( Pt 11):2717-27 PMID: 9820147
  19. Selection of the R17Y substitution in SIVmac239 nef coincided with a dramatic increase in plasma viremia and rapid progression to death.
    Virology. 1999 Feb 1;254(1):61-70 PMID: 9927574
  20. The acidic region and conserved putative protein kinase C phosphorylation site in Nef are important for SIV replication in rhesus macaques.
    Virology. 1999 Apr 25;257(1):138-55 PMID: 10208928
  21. Emergence of CTL coincides with clearance of virus during primary simian immunodeficiency virus infection in rhesus monkeys.
    J Immunol. 1999 May 1;162(9):5127-33 PMID: 10227983
  22. Two elements target SIV Nef to the AP-2 clathrin adaptor complex, but only one is required for the induction of CD4 endocytosis.
    EMBO J. 1999 May 17;18(10):2722-33 PMID: 10329619
  23. Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein.
    Curr Biol. 1999 Jun 17;9(12):613-21 PMID: 10375525
  24. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner.
    Curr Biol. 1999 Jun 17;9(12):622-31 PMID: 10375528
  25. HIV-1 Nef increases T cell activation in a stimulus-dependent manner.
    Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8167-72 PMID: 10393966
  26. The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors.
    Immunol Rev. 1999 Apr;168:51-63 PMID: 10399064
  27. HIV's evasion of the cellular immune response.
    Immunol Rev. 1999 Apr;168:65-74 PMID: 10399065
  28. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages.
    Nat Med. 1999 Sep;5(9):997-103 PMID: 10470075
  29. Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques.
    Curr Biol. 1996 Nov 1;6(11):1519-27 PMID: 8939608
  30. The importance of nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes.
    J Exp Med. 1994 Jan 1;179(1):115-23 PMID: 7903679
  31. Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in vivo in the absence of an intact nef gene.
    J Virol. 1994 Mar;68(3):2031-7 PMID: 8107267
  32. Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes.
    Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1539-43 PMID: 8108442
  33. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene.
    J Virol. 1994 May;68(5):2906-14 PMID: 8151761
  34. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection.
    N Engl J Med. 1995 Jan 26;332(4):228-32 PMID: 7808489
  35. Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4.
    EMBO J. 1995 Feb 1;14(3):484-91 PMID: 7859737
  36. Nef stimulates human immunodeficiency virus type 1 proviral DNA synthesis.
    J Virol. 1995 Aug;69(8):5048-56 PMID: 7541845
  37. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients.
    Science. 1995 Nov 10;270(5238):988-91 PMID: 7481804
  38. Characterization of a CD4-expressing macaque cell line that can detect virus after a single replication cycle and can be infected by diverse simian immunodeficiency virus isolates.
    Virology. 1995 Nov 10;213(2):386-94 PMID: 7491763
  39. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein.
    Nat Med. 1996 Mar;2(3):338-42 PMID: 8612235
  40. Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family.
    J Virol. 1996 Sep;70(9):6157-61 PMID: 8709241
  41. Simian immunodeficiency virus containing mutations in N-terminal tyrosine residues and in the PxxP motif in Nef replicates efficiently in rhesus macaques.
    J Virol. 2000 May;74(9):4155-64 PMID: 10756028
  42. Simian and human immunodeficiency virus Nef proteins use different surfaces to downregulate class I major histocompatibility complex antigen expression.
    J Virol. 2000 Jun;74(12):5691-701 PMID: 10823877
  43. HIV and SIV Nef modulate signal transduction and protein sorting in T cells.
    Cold Spring Harb Symp Quant Biol. 1999;64:453-63 PMID: 11232322
  44. Nef protein of human immunodeficiency virus type 1: evidence against its role as a transcriptional inhibitor.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9549-53 PMID: 2687884
  45. Importance of the nef gene for maintenance of high virus loads and for development of AIDS.
    Cell. 1991 May 17;65(4):651-62 PMID: 2032289
  46. Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA.
    Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5326-30 PMID: 2052609
  47. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene.
    EMBO J. 1993 Feb;12(2):703-13 PMID: 8095017
  48. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor.
    Science. 1993 Jun 25;260(5116):1934-7 PMID: 8316833
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.74.21.9836-9844.2000
Published
2000-11-00
Pages
9836-44
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC102020
Subset
IM
Grants
NIAID NIH HHS · AI-42561 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1128/jvi.74.21.9836-9844.2000 PMC Full Text View journal details
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