title: Net positive charge of HIV-1 CRF01_AE V3 sequence regulates viral sensitivity to humoral immunity.
abstract: 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.
authors.affiliation: Department of Public Health, Yokohama City University School of Medicine, Kanagawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Naganawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Teiichiro
authors.initials: T
authors.lastname: Shiino
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Ueda
authors.forename: Akira
authors.initials: A
authors.lastname: Shirai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takeno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hayakawa
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Sato
authors.forename: Osamu
authors.initials: O
authors.lastname: Tochikubo
authors.forename: Shingo
authors.initials: S
authors.lastname: Kiyoura
authors.forename: Kaori
authors.initials: K
authors.lastname: Sawada
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikegami
authors.forename: Tadahito
authors.initials: T
authors.lastname: Kanda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kitamura
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
mesh_terms: 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
chemical_list: D015699:HIV Envelope Protein gp120
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