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. 1997 May;71(5):4161–4164. doi: 10.1128/jvi.71.5.4161-4164.1997

Deletion of nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human-PBL-SCID mice.

R J Gulizia 1, R G Collman 1, J A Levy 1, D Trono 1, D E Mosier 1
PMCID: PMC191576  PMID: 9094701

Abstract

The pathogenicity of four human immunodeficiency virus type 1 (HIV-1) isolates with nef deleted for SCID mice repopulated with human peripheral blood leukocytes (hu-PBL-SCID mice) was studied. Deletion of nef led to a substantial reduction in CD4-positive T-cell depletion and delayed kinetics of plasma viremia in infected hu-PBL-SCID mice. Deletion of the nef gene impacts both the efficiency of primary infection and the cytopathicity of virus for infected CD4-positive T cells in this animal model of HIV-1 infection.

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Selected References

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  1. Aiken C., Konner J., Landau N. R., Lenburg M. E., Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell. 1994 Mar 11;76(5):853–864. doi: 10.1016/0092-8674(94)90360-3. [DOI] [PubMed] [Google Scholar]
  2. Aldrovandi G. M., Feuer G., Gao L., Jamieson B., Kristeva M., Chen I. S., Zack J. A. The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993 Jun 24;363(6431):732–736. doi: 10.1038/363732a0. [DOI] [PubMed] [Google Scholar]
  3. Aldrovandi G. M., Zack J. A. Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice. J Virol. 1996 Mar;70(3):1505–1511. doi: 10.1128/jvi.70.3.1505-1511.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Balliet J. W., Kolson D. L., Eiger G., Kim F. M., McGann K. A., Srinivasan A., Collman R. Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate. Virology. 1994 May 1;200(2):623–631. doi: 10.1006/viro.1994.1225. [DOI] [PubMed] [Google Scholar]
  5. Bandres J. C., Shaw A. S., Ratner L. HIV-1 Nef protein downregulation of CD4 surface expression: relevance of the lck binding domain of CD4. Virology. 1995 Feb 20;207(1):338–341. doi: 10.1006/viro.1995.1089. [DOI] [PubMed] [Google Scholar]
  6. Baur A. S., Sawai E. T., Dazin P., Fantl W. J., Cheng-Mayer C., Peterlin B. M. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity. 1994 Aug;1(5):373–384. doi: 10.1016/1074-7613(94)90068-x. [DOI] [PubMed] [Google Scholar]
  7. Bodéus M., Marie-Cardine A., Bougeret C., Ramos-Morales F., Benarous R. In vitro binding and phosphorylation of human immunodeficiency virus type 1 Nef protein by serine/threonine protein kinase. J Gen Virol. 1995 Jun;76(Pt 6):1337–1344. doi: 10.1099/0022-1317-76-6-1337. [DOI] [PubMed] [Google Scholar]
  8. Bonyhadi M. L., Rabin L., Salimi S., Brown D. A., Kosek J., McCune J. M., Kaneshima H. HIV induces thymus depletion in vivo. Nature. 1993 Jun 24;363(6431):728–732. doi: 10.1038/363728a0. [DOI] [PubMed] [Google Scholar]
  9. Chowers M. Y., Pandori M. W., Spina C. A., Richman D. D., Guatelli J. C. The growth advantage conferred by HIV-1 nef is determined at the level of viral DNA formation and is independent of CD4 downregulation. Virology. 1995 Oct 1;212(2):451–457. doi: 10.1006/viro.1995.1502. [DOI] [PubMed] [Google Scholar]
  10. Collette Y., Chang H. L., Cerdan C., Chambost H., Algarte M., Mawas C., Imbert J., Burny A., Olive D. Specific Th1 cytokine down-regulation associated with primary clinically derived human immunodeficiency virus type 1 Nef gene-induced expression. J Immunol. 1996 Jan 1;156(1):360–370. [PubMed] [Google Scholar]
  11. Collman R., Balliet J. W., Gregory S. A., Friedman H., Kolson D. L., Nathanson N., Srinivasan A. An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J Virol. 1992 Dec;66(12):7517–7521. doi: 10.1128/jvi.66.12.7517-7521.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  13. Du Z., Lang S. M., Sasseville V. G., Lackner A. A., Ilyinskii P. O., Daniel M. D., Jung J. U., Desrosiers R. C. Identification of a nef allele that causes lymphocyte activation and acute disease in macaque monkeys. Cell. 1995 Aug 25;82(4):665–674. doi: 10.1016/0092-8674(95)90038-1. [DOI] [PubMed] [Google Scholar]
  14. Gallay P., Stitt V., Mundy C., Oettinger M., Trono D. Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import. J Virol. 1996 Feb;70(2):1027–1032. doi: 10.1128/jvi.70.2.1027-1032.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  16. Graziani A., Galimi F., Medico E., Cottone E., Gramaglia D., Boccaccio C., Comoglio P. M. The HIV-1 nef protein interferes with phosphatidylinositol 3-kinase activation 1. J Biol Chem. 1996 Mar 22;271(12):6590–6593. doi: 10.1074/jbc.271.12.6590. [DOI] [PubMed] [Google Scholar]
  17. Gulizia R. J., Levy J. A., Mosier D. E. The envelope gp120 gene of human immunodeficiency virus type 1 determines the rate of CD4-positive T-cell depletion in SCID mice engrafted with human peripheral blood leukocytes. J Virol. 1996 Jun;70(6):4184–4187. doi: 10.1128/jvi.70.6.4184-4187.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang Y., Zhang L., Ho D. D. Biological characterization of nef in long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 1995 Dec;69(12):8142–8146. doi: 10.1128/jvi.69.12.8142-8146.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hwang S. S., Boyle T. J., Lyerly H. K., Cullen B. R. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  20. Jamieson B. D., Aldrovandi G. M., Planelles V., Jowett J. B., Gao L., Bloch L. M., Chen I. S., Zack J. A. Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity. J Virol. 1994 Jun;68(6):3478–3485. doi: 10.1128/jvi.68.6.3478-3485.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kestler H. W., 3rd, Ringler D. J., Mori K., Panicali D. L., Sehgal P. K., Daniel M. D., Desrosiers R. C. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651–662. doi: 10.1016/0092-8674(91)90097-i. [DOI] [PubMed] [Google Scholar]
  22. Kirchhoff F., Greenough T. C., Brettler D. B., Sullivan J. L., Desrosiers R. C. 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):228–232. doi: 10.1056/NEJM199501263320405. [DOI] [PubMed] [Google Scholar]
  23. Levy J. A., Hoffman A. D., Kramer S. M., Landis J. A., Shimabukuro J. M., Oshiro L. S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science. 1984 Aug 24;225(4664):840–842. doi: 10.1126/science.6206563. [DOI] [PubMed] [Google Scholar]
  24. Luciw P. A., Cheng-Mayer C., Levy J. A. Mutational analysis of the human immunodeficiency virus: the orf-B region down-regulates virus replication. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1434–1438. doi: 10.1073/pnas.84.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mariani R., Kirchhoff F., Greenough T. C., Sullivan J. L., Desrosiers R. C., Skowronski J. 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):7752–7764. doi: 10.1128/jvi.70.11.7752-7764.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Michael N. L., Chang G., d'Arcy L. A., Ehrenberg P. K., Mariani R., Busch M. P., Birx D. L., Schwartz D. H. Defective accessory genes in a human immunodeficiency virus type 1-infected long-term survivor lacking recoverable virus. J Virol. 1995 Jul;69(7):4228–4236. doi: 10.1128/jvi.69.7.4228-4236.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Michael N. L., Chang G., d'Arcy L. A., Tseng C. J., Birx D. L., Sheppard H. W. Functional characterization of human immunodeficiency virus type 1 nef genes in patients with divergent rates of disease progression. J Virol. 1995 Nov;69(11):6758–6769. doi: 10.1128/jvi.69.11.6758-6769.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miller M. D., Warmerdam M. T., Gaston I., Greene W. C., Feinberg M. B. 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):101–113. doi: 10.1084/jem.179.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mosier D. E., Gulizia R. J., Baird S. M., Wilson D. B., Spector D. H., Spector S. A. Human immunodeficiency virus infection of human-PBL-SCID mice. Science. 1991 Feb 15;251(4995):791–794. doi: 10.1126/science.1990441. [DOI] [PubMed] [Google Scholar]
  30. Mosier D. E., Gulizia R. J., MacIsaac P. D., Corey L., Greenberg P. D. Resistance to human immunodeficiency virus 1 infection of SCID mice reconstituted with peripheral blood leukocytes from donors vaccinated with vaccinia gp160 and recombinant gp160. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2443–2447. doi: 10.1073/pnas.90.6.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mosier D. E., Gulizia R. J., MacIsaac P. D., Torbett B. E., Levy J. A. Rapid loss of CD4+ T cells in human-PBL-SCID mice by noncytopathic HIV isolates. Science. 1993 Apr 30;260(5108):689–692. doi: 10.1126/science.8097595. [DOI] [PubMed] [Google Scholar]
  32. Mosier D. E. Human immunodeficiency virus infection of human cells transplanted to severe combined immunodeficient mice. Adv Immunol. 1996;63:79–125. doi: 10.1016/s0065-2776(08)60855-x. [DOI] [PubMed] [Google Scholar]
  33. Saksela K., Cheng G., Baltimore D. 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):484–491. doi: 10.1002/j.1460-2075.1995.tb07024.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sanchez-Pescador R., Power M. D., Barr P. J., Steimer K. S., Stempien M. M., Brown-Shimer S. L., Gee W. W., Renard A., Randolph A., Levy J. A. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science. 1985 Feb 1;227(4686):484–492. doi: 10.1126/science.2578227. [DOI] [PubMed] [Google Scholar]
  35. Sawai E. T., Baur A., Struble H., Peterlin B. M., Levy J. A., Cheng-Mayer C. 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):1539–1543. doi: 10.1073/pnas.91.4.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schwartz O., Maréchal V., Le Gall S., Lemonnier F., Heard J. M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med. 1996 Mar;2(3):338–342. doi: 10.1038/nm0396-338. [DOI] [PubMed] [Google Scholar]
  37. Smith B. L., Krushelnycky B. W., Mochly-Rosen D., Berg P. The HIV nef protein associates with protein kinase C theta. J Biol Chem. 1996 Jul 12;271(28):16753–16757. doi: 10.1074/jbc.271.28.16753. [DOI] [PubMed] [Google Scholar]
  38. Spina C. A., Kwoh T. J., Chowers M. Y., Guatelli J. C., Richman D. D. 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):115–123. doi: 10.1084/jem.179.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Terwilliger E. F., Langhoff E., Gabuzda D., Zazopoulos E., Haseltine W. A. Allelic variation in the effects of the nef gene on replication of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10971–10975. doi: 10.1073/pnas.88.23.10971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Terwilliger E., Sodroski J. G., Rosen C. A., Haseltine W. A. Effects of mutations within the 3' orf open reading frame region of human T-cell lymphotropic virus type III (HTLV-III/LAV) on replication and cytopathogenicity. J Virol. 1986 Nov;60(2):754–760. doi: 10.1128/jvi.60.2.754-760.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Torbett B. E., Picchio G., Mosier D. E. hu-PBL-SCID mice: a model for human immune function, AIDS, and lymphomagenesis. Immunol Rev. 1991 Dec;124:139–164. doi: 10.1111/j.1600-065x.1991.tb00620.x. [DOI] [PubMed] [Google Scholar]
  42. Trono D. HIV accessory proteins: leading roles for the supporting cast. Cell. 1995 Jul 28;82(2):189–192. doi: 10.1016/0092-8674(95)90306-2. [DOI] [PubMed] [Google Scholar]

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