Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

• 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
• Journal Title: mBio
• Volume: Volume 6, Number 2
• Publisher: American Society for Microbiology: Open Access Journals | 2015-04-21, Pages e00296-15-e00296-15
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/mBio.00296-15
• Subjects: Biology, Virology; Health Sciences, Immunology; Biology, Microbiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; ANTI-CD4 MONOCLONAL-ANTIBODY; HIV-1 ENVELOPE GLYCOPROTEIN; WESTERN LOWLAND GORILLAS; MEDIATED GENE-TRANSFER; WILD CHIMPANZEES; ANTIRETROVIRAL ACTIVITY; POTENT NEUTRALIZATION; BROAD NEUTRALIZATION; CONGENITAL AMAUROSIS; GP41-GP120 INTERFACE

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.