Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

• Type of Material: Article
• Authors: Hannah J. Barbian, University of Pennsylvania; Julie M. Decker, University of Alabama Birmingham; Frederic Bibollet-Ruche, University of Pennsylvania; Rachel P. Galimidi, California Institute of Technology; Anthony P. West, California Institute of Technology; Gerald H. Learn, University of Pennsylvania; Nicholas F. Parrish, University of Pennsylvania; Shilpa S. Iyer, University of Pennsylvania; Yingying Li, University of Pennsylvania; Craig S. Pace, Gilead Sciences; Ruijiang Song, Rockefeller University; Yaoxing Huang, Rockefeller University; Thomas N. Denny, Duke University; Hugo Mouquet, Rockefeller University; Loic Martin, Service d’Ingénierie Moléculaire des Protéines; Priyamvada Acharya, National Institutes of Health; Baoshan Zhang, National Institutes of Health; Peter D. Kwong, National Institutes of Health; John R. Mascola, National Institutes of Health; C. Theo Verrips, QVQ BV; Nika M. Strokappe, University of Utrecht; Lucy Rutten, University of Utrecht; Laura E. McCoy, University College London; Robin A. Weiss, University College London; Corrine S. Brown, Chimp Haven, Inc.; Raven Jackson, Chimp Haven, Inc.; Guido Silvestri, Emory University; Mark Connors, National Institutes of Health; Dennis R. Burton, Scripps Research Institute; George M. Shaw, University of Pennsylvania
• Language: English
• Date: 2015-04-21
• Publisher: American Society for Microbiology: Open Access Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Barbian et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.00296-15
• Title of Journal or Parent Work: mBio
• ISSN: 2150-7511
• Volume: 6
• Issue: 2
• Start Page: e00296-15
• End Page: e00296-15
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (R37 AI 50529, R01 AI 58715, R37 AI 066998, P01 AI 088564, P51 RR 000165, and P30 AI 045008).
• Keywords: ANTIRETROVIRAL ACTIVITY; WESTERN LOWLAND GORILLAS; HIV-1 ENVELOPE GLYCOPROTEIN; Microbiology; POTENT NEUTRALIZATION; GP41-GP120 INTERFACE; Life Sciences & Biomedicine; CONGENITAL AMAUROSIS; WILD CHIMPANZEES; BROAD NEUTRALIZATION; ANTI-CD4 MONOCLONAL-ANTIBODY; MEDIATED GENE-TRANSFER; Science & Technology
• Research Categories: Biology, Virology; Biology, Microbiology; Health Sciences, Immunology

Abstract

Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n=11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n=1). We found that bNabs directed against the CD4 binding site (n_10), peptidoglycans at the base of variable loop 3 (V3) (n=5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n=5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n=3) as well as llama-derived (heavy chain only) antibodies (n=6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized>90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4_ T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection.