Abstract

This work describes targeted mutations applied to several HIV-1 neutralizing antibodies that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency, which are based on the crystal structures. These modifications are tested against a panel of HIV-1 viruses to determine the breadth and strength of their ability to neutralize. The most potent of these candidates are then selected for testing in in vivo models with the long term goal of testing in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAI005122-01
Application #
8556125
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2012
Total Cost
$1,800,000
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Ferrando-Martinez, Sara; Moysi, Eirini; Pegu, Amarendra et al. (2018) Accumulation of follicular CD8+ T cells in pathogenic SIV infection. J Clin Invest 128:2089-2103
Julg, Boris; Sok, Devin; Schmidt, Stephen D et al. (2017) Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys. J Virol 91:
Petrovas, Constantinos; Ferrando-Martinez, Sara; Gerner, Michael Y et al. (2017) Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med 9:
Julg, Boris; Pegu, Amarendra; Abbink, Peter et al. (2017) Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys. J Virol 91:
Pegu, Amarendra; Asokan, Mangaiarkarasi; Wu, Lan et al. (2015) Activation and lysis of human CD4 cells latently infected with HIV-1. Nat Commun 6:8447
Asokan, M; Rudicell, R S; Louder, M et al. (2015) Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization. J Virol 89:12501-12
Ko, Sung-Youl; Pegu, Amarendra; Rudicell, Rebecca S et al. (2014) Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514:642-5
Rudicell, Rebecca S; Kwon, Young Do; Ko, Sung-Youl et al. (2014) Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J Virol 88:12669-82
Georgiev, Ivelin S; Rudicell, Rebecca S; Saunders, Kevin O et al. (2014) Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with Ig-framework regions substantially reverted to germline. J Immunol 192:1100-1106