Increased sensitivity of HIV variants selected by attachment inhibitors to broadly neutralizing antibodies.
Treatment with HIV attachment inhibitors (AIs) can select for escape mutants throughout the viral envelope. We report on three such mutations: F423Y (gp120 CD4 binding pocket) and I595F and K655E (gp41 ectodomain). Each displayed decreased sensitivity to the AI BMS-488043 and earlier generation AIs, along with increased sensitivity to the broadly neutralizing antibodies 2F5 and 4E10, without affecting the rate of viral entry or sensitivity to the entry inhibitors AMD-3100 and Enfuvirtide. We also observed that I595F did not substantially increase envelope sensitivity to HIV-infected patient sera. Based on these observations, we propose that although F423Y, I595F and K655E may all affect the presentation of the 2F5 and 4E10 epitopes, natural immune mimicry is rare only for the I595F effect. Thus, it seems that in addition to restricting AI resistance development, incorporation of I595F into an appropriate vehicle could elicit a novel antiviral response to improve vaccine efficacy.
Zhou
Nannan
N
Department of Virology, 5 Department of Research Parkway, Wallingford, CT 06498, USA.
Fan
Li
L
Ho
Hsu-Tso
HT
Nowicka-Sans
Beata
B
Sun
Yongnian
Y
Zhu
Yingjie
Y
Hu
Yanhua
Y
McAuliffe
Brian
B
Rose
Burt
B
Fang
Hua
H
Wang
Tao
T
Kadow
John
J
Krystal
Mark
M
Alexander
Louis
L
Colonno
Richard
R
Lin
Pin-Fang
PF
D057134:Antibodies, Neutralizing / Q000276:immunology*; D024882:Drug Resistance, Viral; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007211:Indoles; D015394:Molecular Structure; D020125:Mutation, Missense; D009500:Neutralization Tests; D010879:Piperazines / Q000494:pharmacology; D019289:Pyruvic Acid
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; D019289:Pyruvic Acid; C509651:BMS-488043