Counteraction of HLA-C-mediated immune control of HIV-1 by Nef.
A host genetic variant (-35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective -35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the "protective" high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective -35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the -35TT genotype. Since the latter Nef functions all influence the stimulation of CD4(+) T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common -35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation.
Specht
Anke
A
Institute of Molecular Virology, University Hospital of Ulm, Meyerhofstr. 1, 89081 Ulm, Germany.
Telenti
Amalio
A
Martinez
Raquel
R
Fellay
Jacques
J
Bailes
Elizabeth
E
Evans
David T
DT
Carrington
Mary
M
Hahn
Beatrice H
BH
Goldstein
David B
DB
Kirchhoff
Frank
F
D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005838:Genotype; D015497:HIV-1 / Q000276:immunology*; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D016827:CD8 Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D050778:NFATC Transcription Factors; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus
J Virol. 1994 May;68(5):2906-14
8151761
Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8167-72
10393966
Science. 1995 Nov 10;270(5238):988-91
7481804
Nat Genet. 2009 Dec;41(12):1290-4
19935663
J Virol. 2008 Mar;82(6):3139-46
18199657
J Virol. 2005 Aug;79(16):10650-9
16051857
J Clin Invest. 1999 Sep;104(5):611-8
10487775
Science. 2007 Aug 17;317(5840):944-7
17641165
J Virol. 2004 Dec;78(23):13335-44
15542684
J Virol. 2002 Jul;76(13):6425-34
12050354
PLoS Genet. 2009 Dec;5(12):e1000791
20041166
J Virol. 2001 Nov;75(21):10532-6
11581427
J Exp Med. 1994 Jan 1;179(1):115-23
7903679
J Biol Chem. 2004 Sep 17;279(38):39520-31
15258149
PLoS Pathog. 2007 Jul;3(7):e94
17616974
Curr HIV Res. 2008 May;6(3):200-8
18473783
J Virol. 1999 Jan;73(1):436-43
9847349
J Immunol. 2008 Jan 15;180(2):1107-16
18178851
Nat Med. 2003 Jul;9(7):853-60
12835705
Int J Cancer. 1980 Aug;26(2):171-6
6970727
Virology. 2008 Mar 30;373(1):229-37
18155264
Immunity. 1999 Jun;10(6):661-71
10403641
N Engl J Med. 1995 Jan 26;332(4):228-32
7808489
J Immunol. 2005 Nov 1;175(9):6050-7
16237100
Nature. 1998 Jan 22;391(6665):397-401
9450757
J Virol. 2005 May;79(9):5489-98
15827163
Curr HIV Res. 2003 Apr;1(2):167-84
15043201
EMBO Rep. 2001 Jul;2(7):580-5
11463741
EMBO J. 1997 Feb 17;16(4):673-84
9049297
Cell Mol Life Sci. 2008 Sep;65(17):2621-36
18438604
J Virol. 2003 Oct;77(19):10548-56
12970439
J Mol Biol. 1994 Sep 2;241(5):651-62
7520946
J Exp Med. 1994 Jan 1;179(1):101-13
8270859
J Virol. 2001 Apr;75(8):3657-65
11264355
Cell. 1991 May 17;65(4):651-62
2032289
Microbiol Mol Biol Rev. 2006 Jun;70(2):548-63
16760313
AIDS. 2007 May 31;21(9):1103-7
17502720
PLoS Pathog. 2008 Jul 18;4(7):e1000107
18636106
J Immunol. 2003 Oct 15;171(8):3999-4005
14530319
Cell. 1994 Jan 28;76(2):263-74
8293463
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12144-9
11593029
J Immunol. 2008 Mar 15;180(6):4075-81
18322217
Cell. 2006 Jun 16;125(6):1055-67
16777597
Nucleic Acids Res. 1997 Dec 15;25(24):4876-82
9396791
J Virol. 2007 Dec;81(24):13852-64
17928336