Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.
BACKGROUND
Despite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C.


RESULTS
Individuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses. Using methods that account for founder effects and HLA linkage disequilibrium, we identified 35 AA sites under Human Leukocyte Antigen (HLA)-restricted CTL selection pressure and 534 AA-to-AA interactions. Analysis of two-dimensional distances between co-varying residues revealed local stabilization mechanisms since 40% of associations involved neighboring residues. Key features of our co-variation analysis included sites with a high number of co-varying partners, such as HLA-associated sites, which had on average 55% more connections than other co-varying sites.


CONCLUSIONS
Clusters of co-varying AA around HLA-associated sites (especially at typically conserved sites) suggested that cooperative interactions act to preserve the local structural stability and protein function when CTL escape mutations occur. These results expose HLA-imprinted HIV-1 polymorphisms and their interlinked mutational paths in Gag that are likely due to opposite selective pressures from host CTL-mediated responses and viral fitness constraints.
Rolland
Morgane
M
Department of Microbiology, University of Washington, Seattle, Washington, United States of America. mrolland@u.washington.edu
Carlson
Jonathan M
JM
Manocheewa
Siriphan
S
Swain
J Victor
JV
Lanxon-Cookson
Erinn
E
Deng
Wenjie
W
Rousseau
Christine M
CM
Raugi
Dana N
DN
Learn
Gerald H
GH
Maust
Brandon S
BS
Coovadia
Hoosen
H
Ndung'u
Thumbi
T
Goulder
Philip J R
PJ
Walker
Bruce D
BD
Brander
Christian
C
Heckerman
David E
DE
Mullins
James I
JI
D000595:Amino Acid Sequence; D044383:Black People / Q000235:genetics; D002460:Cell Line; D015331:Cohort Studies; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013019:South Africa; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D006680:HLA Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus
J Virol. 2008 Jun;82(11):5594-605
18385228
J Exp Med. 2004 Apr 5;199(7):905-15
15067030
J Virol. 2008 Sep;82(17):8422-30
18562530
PLoS Comput Biol. 2006 Jul 14;2(7):e88
16839197
Science. 2007 Mar 16;315(5818):1583-6
17363674
PLoS One. 2007 Oct 03;2(10):e984
17912361
J Virol. 2008 Jul;82(13):6434-46
18434400
PLoS Comput Biol. 2008 Nov;4(11):e1000225
19023406
Syst Biol. 2003 Oct;52(5):696-704
14530136
Virology. 2003 Sep 30;314(2):536-48
14554082
J Virol. 2005 Nov;79(22):13953-62
16254331
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
J Virol. 2008 Sep;82(17):8548-59
18596105
Biochem Genet. 1970 Oct;4(5):579-93
5489762
Science. 1964 Dec 18;146(3651):1593-4
14224506
J Virol. 2003 Apr;77(8):4836-47
12663790
PLoS Pathog. 2007 Jul;3(7):e94
17616974
PLoS Pathog. 2009 Apr;5(4):e1000365
19343217
Genome Res. 2007 Aug;17(8):1195-201
17600086
EMBO J. 1998 Mar 16;17(6):1555-68
9501077
Antimicrob Agents Chemother. 2005 May;49(5):2015-25
15855527
J Exp Med. 2005 Mar 21;201(6):891-902
15781581
J Virol. 2007 Nov;81(22):12608-18
17728232
J Virol. 2009 Jan;83(1):140-9
18971283
Methods Mol Biol. 2003;224:149-57
12710672
Nat Med. 2007 Jan;13(1):46-53
17173051
J Virol. 2007 Nov;81(22):12382-93
17804494
Nat Med. 2004 Mar;10(3):282-9
14770175
J Virol. 2006 Mar;80(5):2380-9
16474144
J Virol Methods. 2006 Sep;136(1-2):118-25
16701907
Curr Drug Targets Infect Disord. 2003 Dec;3(4):355-71
14754435
AIDS. 2003 Apr 11;17(6):791-9
12660525
PLoS Pathog. 2007 Nov;3(11):e157
18052528
Antiviral Res. 2006 Sep;71(2-3):293-300
16806514
PLoS One. 2007 Jul 04;2(7):e591
17611623
Bioinformatics. 2005 Mar 1;21(5):676-9
15509596
J Virol. 2007 May;81(9):4492-500
17314156
J Virol. 2007 Aug;81(15):8346-51
17507468
J Acquir Immune Defic Syndr. 2002 Apr 15;29(5):429-34
11981357
PLoS Pathog. 2007 Mar;3(3):e45
17397261