Net positive charge of HIV-1 CRF01_AE V3 sequence regulates viral sensitivity to humoral immunity.
The third variable region (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope gp120 subunit participates in determination of viral infection coreceptor tropism and host humoral immune responses. Positive charge of the V3 plays a key role in determining viral coreceptor tropism. Here, we examined by bioinformatics, experimental, and protein modelling approaches whether the net positive charge of V3 sequence regulates viral sensitivity to humoral immunity. We chose HIV-1 CRF01_AE strain as a model virus to address the question. Diversity analyses using CRF01_AE V3 sequences from 37 countries during 1984 and 2005 (n = 1361) revealed that reduction in the V3's net positive charge makes V3 less variable due to limited positive selection. Consistently, neutralization assay using CRF01_AE V3 recombinant viruses (n = 30) showed that the reduction in the V3's net positive charge rendered HIV-1 less sensitive to neutralization by the blood anti-V3 antibodies. The especially neutralization resistant V3 sequences were the particular subset of the CCR5-tropic V3 sequences with net positive charges of +2 to +4. Molecular dynamics simulation of the gp120 monomers showed that the V3's net positive charge regulates the V3 configuration. This and reported gp120 structural data predict a less-exposed V3 with a reduced net positive charge in the native gp120 trimer context. Taken together, these data suggest a key role of the V3's net positive charge in the immunological escape and coreceptor tropism evolution of HIV-1 CRF01_AE in vivo. The findings have molecular implications for the adaptive evolution and vaccine design of HIV-1.
Naganawa
Satoshi
S
Department of Public Health, Yokohama City University School of Medicine, Kanagawa, Japan.
Yokoyama
Masaru
M
Shiino
Teiichiro
T
Suzuki
Takeyuki
T
Ishigatsubo
Yoshiaki
Y
Ueda
Atsuhisa
A
Shirai
Akira
A
Takeno
Mitsuhiro
M
Hayakawa
Satoshi
S
Sato
Shigehiro
S
Tochikubo
Osamu
O
Kiyoura
Shingo
S
Sawada
Kaori
K
Ikegami
Takashi
T
Kanda
Tadahito
T
Kitamura
Katsuhiko
K
Sato
Hironori
H
D000917:Antibody Formation; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D015233:Models, Statistical; D008968:Molecular Conformation; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D014779:Virus Replication / Q000235:genetics
D015699:HIV Envelope Protein gp120
J Virol. 1992 Nov;66(11):6547-54
1404602
J Comput Chem. 2005 Dec;26(16):1668-88
16200636
Biochem Biophys Res Commun. 1999 May 10;258(2):313-21
10329384
Antimicrob Agents Chemother. 2001 Feb;45(2):495-501
11158746
Cell. 1996 Jun 28;85(7):1135-48
8674119
Science. 2000 Apr 7;288(5463):55-6
10766634
J Virol. 1998 May;72(5):3512-9
9557629
J Virol. 1997 Sep;71(9):7136-9
9261451
J Virol. 2000 May;74(9):4404-13
10756055
Nat Med. 1997 Nov;3(11):1259-65
9359702
J Virol. 2001 Jun;75(12):5604-13
11356968
Science. 1991 Jul 5;253(5015):71-4
1905842
J Virol. 1999 May;73(5):3551-9
10196244
J Virol. 2005 Jun;79(11):6957-68
15890935
J Virol. 2007 Jul;81(13):6798-806
17459935
Virology. 1991 Dec;185(2):661-72
1683726
J Infect Dis. 1995 Sep;172(3):851-4
7658081
Bioinformatics. 2003 Dec 12;19(18):2496-7
14668244
J Virol. 1995 Mar;69(3):1810-8
7853521
AIDS. 2002 Dec 6;16(18):2409-17
12461414
MD Comput. 1997 Jul-Aug;14(4):306-17
9230594
Science. 1998 Jun 19;280(5371):1949-53
9632396
J Virol. 2007 Jul;81(13):7280-5
17475650
Virology. 1999 May 10;257(2):491-501
10329559
J Virol. 1999 Jul;73(7):5520-6
10364300
J Virol. 1997 Apr;71(4):2779-85
9060632
Mol Biol Evol. 1986 Sep;3(5):418-26
3444411
J Virol. 1995 Oct;69(10):6191-8
7545244
J Virol. 2000 Feb;74(3):1069-78
10627516
J Exp Med. 1997 Feb 17;185(4):621-8
9034141
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10018-23
9294155
Mol Biol Evol. 1994 Jul;11(4):613-9
8078400
Nat Med. 1999 Jul;5(7):723-5
10395309
J Virol. 1990 Dec;64(12):5840-50
2243378
J Virol. 1994 Sep;68(9):6006-13
8057475
Science. 2005 Nov 11;310(5750):1025-8
16284180
AIDS Res Hum Retroviruses. 2002 Jan 20;18(2):115-22
11839144
Nature. 1995 Jul 13;376(6536):125
7603560
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1264-9
9037041
AIDS. 1993 Mar;7(3):337-40
8471195
Science. 2007 Sep 28;317(5846):1930-4
17901336
J Virol. 1993 Sep;67(9):5623-34
8350415
Nature. 1998 Jan 15;391(6664):240
9440686
AIDS Res Hum Retroviruses. 1997 Dec 10;13(18):1597-609
9430252
Nature. 2006 Jun 15;441(7095):847-52
16728975
AIDS Res Hum Retroviruses. 2007 Mar;23(3):415-26
17411375
J Virol. 1995 Jan;69(1):101-9
7527081
Genetics. 1989 Nov;123(3):585-95
2513255