Induction of primary virus-cross-reactive human immunodeficiency virus type 1-neutralizing antibodies in small animals by using an alphavirus-derived in vivo expression system.
We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160deltaCT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160deltaCT was released by cells in the form of membrane-bound vesicles. gp160deltaCT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.
Dong
Ming
M
Departments of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda 20814, USA.
Zhang
Peng Fei
PF
Grieder
Franziska
F
Lee
James
J
Krishnamurthy
Govindaraj
G
VanCott
Thomas
T
Broder
Christopher
C
Polonis
Victoria R
VR
Yu
Xiao-Fang
XF
Shao
Yiming
Y
Faix
Dennis
D
Valente
Patricia
P
Quinnan
Gerald V
GV
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D003429:Cross Reactions; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics / Q000276:immunology*; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011817:Rabbits; D012093:Replicon / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160