Abstract

HIV-1 is primarily transmitted via the mucosal route. Therefore we have used a nonhuman primate model of mucosal SHIV infection to assess the efficacy of various anti-HIV-1 bnAbs. We have shown that the anti-HIV-1 bnAbs VRC01 and 10E8 that target the CD4 binding site(CD4bs) and the Membrane proximal region (MPER)on the HIV-1 envelope glycoprotein, respectively, can effectively protect nonhuman primates against mucosal SHIV challenge when administered at very low doses to these animals before mucosal challenge with a pathogenic SHIV1. Furthermore, we have demonstrated that adding a Fc mutation that increases binding to the neonatal Fc receptor improves the serum half life and mucosal retention of VRC01 in nonhuman primates2. This mutation also leads to increased protective efficacy against a mucosal challenge with SHIV. In addition, through a combination of next-generation sequencing, computational bioinformatics, and structure-guided design, we have developed a more potent version of VRC01, VRC07-523-LS3. VRC07-523-LS exhibits about a 5-8 fold increase in in vitro neutralization potency compared to VRC01, and it provided protection to nonhuman primates at 5-fold lower concentrations than VRC01 against a mucosal challenge with SHIV.

  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 #
1ZIAAI005009-13
Application #
8946566
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Hessell, Ann J; Jaworski, J Pablo; Epson, Erin et al. (2016) Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med 22:362-8
Bolton, Diane L; Pegu, Amarendra; Wang, Keyun et al. (2016) Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs. J Virol 90:1321-32
Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra et al. (2016) A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105-109
Saunders, Kevin O; Pegu, Amarendra; Georgiev, Ivelin S et al. (2015) Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection. J Virol 89:5895-903
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
Pegu, Amarendra; Yang, Zhi-yong; Boyington, Jeffrey C et al. (2014) Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci Transl Med 6:243ra88
Flatz, Lukas; Cheng, Cheng; Wang, Lingshu et al. (2012) Gene-based vaccination with a mismatched envelope protects against simian immunodeficiency virus infection in nonhuman primates. J Virol 86:7760-70
Gautam, Rajeev; Nishimura, Yoshiaki; Lee, Wendy R et al. (2012) Pathogenicity and mucosal transmissibility of the R5-tropic simian/human immunodeficiency virus SHIV(AD8) in rhesus macaques: implications for use in vaccine studies. J Virol 86:8516-26
Yeh, Wendy W; Brassard, Laura M; Miller, Caroline A et al. (2012) Envelope variable region 4 is the first target of neutralizing antibodies in early simian immunodeficiency virus mac251 infection of rhesus monkeys. J Virol 86:7052-9

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