Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression
Martin Tolstrup A B D , Alex L. Laursen A , Jan Gerstoft C , Finn S. Pedersen B , Lars Ostergaard A and Mogens Duch BA Department of Infectious Diseases, Skejby Hospital, 8200 Aarhus, Denmark.
B Department of Molecular Biology, University of Aarhus, 8000 Aarhus, Denmark.
C Department of Epidemiology, Rigshospitalet, 2100 Copenhagen, Denmark.
D Corresponding author. Email: mt@mb.au.dk
Sexual Health 3(4) 281-286 https://doi.org/10.1071/SH06002
Submitted: 5 January 2006 Accepted: 10 April 2006 Published: 17 November 2006
Abstract
Background: The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. Methods: The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. Results: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. Conclusion: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337–45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.
Acknowledgements
The authors’ wish to thank Jonna Guldberg for excellent technical assistance. MT is a scholar at the research school in Genetic Medicine. The project was supported by the Danish AIDS Foundation.
[1] Premkumar DR, Ma XZ, Maitra RK, Chakrabarti BK, Salkowitz J, Yen-Lieberman B, et al. The nef gene from a long-term HIV type 1 nonprogressor. AIDS Res Hum Retroviruses 1996; 12(4): 337–45.
| PubMed |
[2] Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci USA 2000; 97(6): 2709–14.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[3] Fang G, Kuiken C, Weiser B, Rowland-Jones S, Plummer F, Chen CH, et al. Long-term survivors in Nairobi: complete HIV-1 RNA sequences and immunogenetic associations. J Infect Dis 2004; 190(4): 697–701.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[4] Stewart GJ, Ashton LJ, Biti RA, Ffrench RA, Bennetts BH, Newcombe NR, et al. Increased frequency of CCR-5 delta 32 heterozygotes among long-term non-progressors with HIV-1 infection. The Australian Long-Term Non-Progressor Study Group. AIDS 1997; 11(15): 1833–8.
| PubMed |
[5] Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307(5714): 1434–40.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[6] Alexander L, Aquino-DeJesus MJ, Chan M, Andiman WA. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by a two-amino-acid insertion in HIV-1 Vif from a nonprogressing mother and child. J Virol 2002; 76(20): 10533–9.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[7] Fang G, Burger H, Chappey C, Rowland-Jones S, Visosky A, Chen CH, et al. Analysis of transition from long-term nonprogressive to progressive infection identifies sequences that may attenuate HIV type 1. AIDS Res Hum Retroviruses 2001; 17(15): 1395–404.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[8] Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995; 270(5238): 988–91.
| PubMed |
[9] 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; 332(4): 228–32.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[10] Kirchhoff F, Easterbrook PJ, Douglas N, Troop M, Greenough TC, Weber J, et al. Sequence variations in human immunodeficiency virus type 1 Nef are associated with different stages of disease. J Virol 1999; 73(7): 5497–508.
| PubMed |
[11] Mariani R, Kirchhoff F, Greenough TC, Sullivan JL, Desrosiers RC, Skowronski J. High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection. J Virol 1996; 70(11): 7752–64.
| PubMed |
[12] Rhodes DI, Ashton L, Solomon A, Carr A, Cooper D, Kaldor J, et al. Characterization of three nef-defective human immunodeficiency virus type 1 strains associated with long-term nonprogression. Australian Long-Term Nonprogressor Study Group. J Virol 2000; 74(22): 10581–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[13] Novembre FJ, Lewis MG, Saucier MM, Yalley-Ogunro J, Brennan T, McKinnon K, et al. Deletion of the nef gene abrogates the ability of SIV smmPBj to induce acutely lethal disease in pigtail macaques. AIDS Res Hum Retroviruses 1996; 12(8): 727–36.
| PubMed |
[14] Whatmore AM, Cook N, Hall GA, Sharpe S, Rud EW, Cranage MP. Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence. J Virol 1995; 69(8): 5117–23.
| PubMed |
[15] Lindemann D, Wilhelm R, Renard P, Althage A, Zinkernagel R, Mous J. Severe immunodeficiency associated with a human immunodeficiency virus 1 NEF/3′-long terminal repeat transgene. J Exp Med 1994; 179(3): 797–807.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[16] Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, et al. Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. N Engl J Med 1999; 340(22): 1715–22.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[17] Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M. HIV/SIV escape from immune surveillance: focus on Nef. Curr HIV Res 2004; 2(2): 141–51.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[18] 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; 177(6): 1561–6.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[19] Bresnahan PA, Yonemoto W, Ferrell S, Williams-Herman D, Geleziunas R, Greene WC. A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor. Curr Biol 1998; 8(22): 1235–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[20] Piguet V, Chen YL, Mangasarian A, Foti M, Carpentier JL, Trono D. Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes. EMBO J 1998; 17(9): 2472–81.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[21] Stoddart CA, Geleziunas R, Ferrell S, Linquist-Stepps V, Moreno ME, Bare C, et al. Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis. J Virol 2003; 77(3): 2124–33.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[22] Saitou N, Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 1987; 4(4): 406–25.
| PubMed |
[23]
[24] Wu L, Paxton WA, Kassam N, Ruffing N, Rottman JB, Sullivan N, et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J Exp Med 1997; 185(9): 1681–91.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[25] Blagoveshchenskaya AD, Thomas L, Feliciangeli SF, Hung CH, Thomas G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 2002; 111(6): 853–66.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[26] Freund J, Kellner R, Konvalinka J, Wolber V, Krausslich HG, Kalbitzer HR. A possible regulation of negative factor (Nef) activity of human immunodeficiency virus type 1 by the viral protease. Eur J Biochem 1994; 223(2): 589–93.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[27] Zazopoulos E, Haseltine WA. Mutational analysis of the human immunodeficiency virus type 1 Eli Nef function. Proc Natl Acad Sci USA 1992; 89(14): 6634–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[28] Yamada T, Iwamoto A. Comparison of proviral accessory genes between long-term nonprogressors and progressors of human immunodeficiency virus type 1 infection. Arch Virol 2000; 145(5): 1021–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[29] Tobiume M, Takahoko M, Yamada T, Tatsumi M, Iwamoto A, Matsuda M. Inefficient enhancement of viral infectivity and CD4 downregulation by human immunodeficiency virus type 1 Nef from Japanese long-term nonprogressors. J Virol 2002; 76(12): 5959–65.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[30]
[31] Hahn T, Ramakrishnan R, Ahmad N. Evaluation of genetic diversity of human immunodeficiency virus type 1 NEF gene associated with vertical transmission. J Biomed Sci 2003; 10(4): 436–50.
| PubMed |
[32] Wang B, Spira TJ, Owen S, Lal RB, Saksena NK. HIV-1 strains from a cohort of American subjects reveal the presence of a V2 region extension unique to slow progressors and non-progressors. AIDS 2000; 14(3): 213–23.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
[33] McPhee DA, Greenway AL, Holloway G, Smith K, Deacon N, Pemberton L, et al. Anomalies in Nef expression within the central nervous system of HIV-1 positive individuals/AIDS patients with or without AIDS dementia complex. J Neurovirol 1998; 4(3): 291–300.
| PubMed |
