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J Virol. Nov 1996; 70(11): 7752–7764.
PMCID: PMC190845

High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection.

Abstract

A large number of nef alleles were obtained from peripheral blood mononuclear cells (PBMC) of four long-term nonprogressing survivors of human immunodeficiency virus type 1 (HIV-1) infection and from five individuals with progressive HIV-1 infection. These primary nef alleles were characterized by DNA sequence analysis and for their ability to downregulate CD4 surface expression. Intact nef open reading frames that directed the expression of Nef protein were recovered from all of the individuals. Most of the Nef proteins derived from three of four individuals with nonprogressive infection and from all five individuals with progressive infection were functional as judged by their ability to induce a decrease in surface CD4 expression. In contrast, one individual with nonprogressive HIV-1 infection yielded an unusually high frequency of disrupted nef open reading frames and Nef proteins defective for CD4 downregulation. Approximately 70% of the nef clones obtained from the PBMC of this individual at eight time points over a 12-year period were disrupted or defective for CD4 downregulation. While functional Nef proteins were demonstrated early in the course of infection (1983), functional nef alleles have surprisingly not come to predominate over time in PBMC DNA in this individual.

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Selected References

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  • Aiken C, Konner J, Landau NR, Lenburg ME, 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. [PubMed]
  • Aiken C, Trono D. Nef stimulates human immunodeficiency virus type 1 proviral DNA synthesis. J Virol. 1995 Aug;69(8):5048–5056. [PMC free article] [PubMed]
  • Anderson SJ, Lenburg M, Landau NR, Garcia JV. The cytoplasmic domain of CD4 is sufficient for its down-regulation from the cell surface by human immunodeficiency virus type 1 Nef. J Virol. 1994 May;68(5):3092–3101. [PMC free article] [PubMed]
  • Anderson S, Shugars DC, Swanstrom R, Garcia JV. Nef from primary isolates of human immunodeficiency virus type 1 suppresses surface CD4 expression in human and mouse T cells. J Virol. 1993 Aug;67(8):4923–4931. [PMC free article] [PubMed]
  • Benson RE, Sanfridson A, Ottinger JS, Doyle C, Cullen BR. Downregulation of cell-surface CD4 expression by simian immunodeficiency virus Nef prevents viral super infection. J Exp Med. 1993 Jun 1;177(6):1561–1566. [PMC free article] [PubMed]
  • Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD. Long-term HIV-1 infection without immunologic progression. AIDS. 1994 Aug;8(8):1123–1128. [PubMed]
  • Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. [PubMed]
  • Chowers MY, Spina CA, Kwoh TJ, Fitch NJ, Richman DD, Guatelli JC. Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene. J Virol. 1994 May;68(5):2906–2914. [PMC free article] [PubMed]
  • Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science. 1995 Nov 10;270(5238):988–991. [PubMed]
  • Delassus S, Cheynier R, Wain-Hobson S. Evolution of human immunodeficiency virus type 1 nef and long terminal repeat sequences over 4 years in vivo and in vitro. J Virol. 1991 Jan;65(1):225–231. [PMC free article] [PubMed]
  • de Ronde A, Klaver B, Keulen W, Smit L, Goudsmit J. Natural HIV-1 NEF accelerates virus replication in primary human lymphocytes. Virology. 1992 May;188(1):391–395. [PubMed]
  • Garcia JV, Miller AD. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Nature. 1991 Apr 11;350(6318):508–511. [PubMed]
  • Gibbs JS, Lackner AA, Lang SM, Simon MA, Sehgal PK, Daniel MD, Desrosiers RC. Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995 Apr;69(4):2378–2383. [PMC free article] [PubMed]
  • Gojobori T, Moriyama EN, Kimura M. Statistical methods for estimating sequence divergence. Methods Enzymol. 1990;183:531–550. [PubMed]
  • Goldsmith MA, Warmerdam MT, Atchison RE, Miller MD, Greene WC. Dissociation of the CD4 downregulation and viral infectivity enhancement functions of human immunodeficiency virus type 1 Nef. J Virol. 1995 Jul;69(7):4112–4121. [PMC free article] [PubMed]
  • Greenough TC, Somasundaran M, Brettler DB, Hesselton RM, Alimenti A, Kirchhoff F, Panicali D, Sullivan JL. Normal immune function and inability to isolate virus in culture in an individual with long-term human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 1994 Apr;10(4):395–403. [PubMed]
  • Huang Y, Zhang L, Ho DD. Characterization of nef sequences in long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 1995 Jan;69(1):93–100. [PMC free article] [PubMed]
  • Huang Y, Zhang L, Ho DD. Biological characterization of nef in long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 1995 Dec;69(12):8142–8146. [PMC free article] [PubMed]
  • Jamieson BD, Aldrovandi GM, Planelles V, Jowett JB, Gao L, Bloch LM, Chen IS, Zack JA. Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity. J Virol. 1994 Jun;68(6):3478–3485. [PMC free article] [PubMed]
  • Kestler HW, 3rd, Ringler DJ, Mori K, Panicali DL, Sehgal PK, Daniel MD, Desrosiers RC. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651–662. [PubMed]
  • Kimpton J, Emerman M. Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated beta-galactosidase gene. J Virol. 1992 Apr;66(4):2232–2239. [PMC free article] [PubMed]
  • Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC. 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. [PubMed]
  • Learmont J, Tindall B, Evans L, Cunningham A, Cunningham P, Wells J, Penny R, Kaldor J, Cooper DA. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet. 1992 Oct 10;340(8824):863–867. [PubMed]
  • Lifson AR, Buchbinder SP, Sheppard HW, Mawle AC, Wilber JC, Stanley M, Hart CE, Hessol NA, Holmberg SD. Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis. 1991 May;163(5):959–965. [PubMed]
  • Luciw PA, Cheng-Mayer C, Levy JA. 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. [PMC free article] [PubMed]
  • Mariani R, Skowronski J. CD4 down-regulation by nef alleles isolated from human immunodeficiency virus type 1-infected individuals. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5549–5553. [PMC free article] [PubMed]
  • Michael NL, Chang G, d'Arcy LA, Ehrenberg PK, Mariani R, Busch MP, Birx DL, Schwartz DH. 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. [PMC free article] [PubMed]
  • Michael NL, Chang G, d'Arcy LA, Tseng CJ, Birx DL, Sheppard HW. 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. [PMC free article] [PubMed]
  • Miller MD, Warmerdam MT, Gaston I, Greene WC, Feinberg MB. 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. [PMC free article] [PubMed]
  • Muñoz A, Wang MC, Bass S, Taylor JM, Kingsley LA, Chmiel JS, Polk BF. Acquired immunodeficiency syndrome (AIDS)-free time after human immunodeficiency virus type 1 (HIV-1) seroconversion in homosexual men. Multicenter AIDS Cohort Study Group. Am J Epidemiol. 1989 Sep;130(3):530–539. [PubMed]
  • Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, Montefiori D, Orenstein JM, Fox C, Schrager LK, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med. 1995 Jan 26;332(4):209–216. [PubMed]
  • Ratner L, Starcich B, Josephs SF, Hahn BH, Reddy EP, Livak KJ, Petteway SR, Jr, Pearson ML, Haseltine WA, Arya SK, et al. Polymorphism of the 3' open reading frame of the virus associated with the acquired immune deficiency syndrome, human T-lymphotropic virus type III. Nucleic Acids Res. 1985 Nov 25;13(22):8219–8229. [PMC free article] [PubMed]
  • Rhee SS, Marsh JW. Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4. J Virol. 1994 Aug;68(8):5156–5163. [PMC free article] [PubMed]
  • Rutherford GW, Lifson AR, Hessol NA, Darrow WW, O'Malley PM, Buchbinder SP, Barnhart JL, Bodecker TW, Cannon L, Doll LS, et al. Course of HIV-I infection in a cohort of homosexual and bisexual men: an 11 year follow up study. BMJ. 1990 Nov 24;301(6762):1183–1188. [PMC free article] [PubMed]
  • Salghetti S, Mariani R, Skowronski J. Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):349–353. [PMC free article] [PubMed]
  • Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD. Long-term HIV-1 infection without immunologic progression. AIDS. 1994 Aug;8(8):1123–1128. [PubMed]
  • Sheppard HW, Lang W, Ascher MS, Vittinghoff E, Winkelstein W. The characterization of non-progressors: long-term HIV-1 infection with stable CD4+ T-cell levels. AIDS. 1993 Sep;7(9):1159–1166. [PubMed]
  • Shugars DC, Smith MS, Glueck DH, Nantermet PV, Seillier-Moiseiwitsch F, Swanstrom R. Analysis of human immunodeficiency virus type 1 nef gene sequences present in vivo. J Virol. 1993 Aug;67(8):4639–4650. [PMC free article] [PubMed]
  • Skowronski J, Parks D, Mariani R. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. EMBO J. 1993 Feb;12(2):703–713. [PMC free article] [PubMed]
  • Spina CA, Kwoh TJ, Chowers MY, Guatelli JC, Richman DD. 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. [PMC free article] [PubMed]
  • Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. [PubMed]

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