Format

Send to

Choose Destination
J Virol. 2018 Nov 12;92(23). pii: e00895-18. doi: 10.1128/JVI.00895-18. Print 2018 Dec 1.

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs.

Author information

1
Division of Infectious Diseases, Weill Cornell Medical College, New York, New York, USA.
2
Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC, USA.
3
Maple Leaf Medical Clinic, Toronto, Ontario, Canada.
4
NantBioScience Inc./NantKwest LLC, Culver City, California, USA.
5
NantWorks, LLC, Culver City, California, USA.
6
Department of Pediatrics, Albert Einstein College of Medicine, New York, New York, USA.
7
Department of Microbiology & Immunology, Albert Einstein College of Medicine, New York, New York, USA.
8
Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC, USA rmlynch@email.gwu.edu rbjones@med.cornell.edu.
9
Division of Infectious Diseases, Weill Cornell Medical College, New York, New York, USA rmlynch@email.gwu.edu rbjones@med.cornell.edu.
#
Contributed equally

Abstract

Efforts to cure human immunodeficiency virus (HIV) infection are obstructed by reservoirs of latently infected CD4+ T cells that can reestablish viremia. HIV-specific broadly neutralizing antibodies (bNAbs), defined by unusually wide neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, thus targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4+ T cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from antiretroviral (ARV)-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Single-antibody breadths ranged from 0 to 64% for neutralization (80% inhibitory concentration [IC80] of ≤10 μg/ml) and from 0 to 89% for binding, with two-antibody combinations (results for antibody combinations are theoretical/predicted) reaching levels of 0 to 83% and 50 to 100%, respectively. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (e.g., for 3BNC117, r = 0.82 and P < 0.0001). Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies, both by providing a direct assessment of intra- and interindividual variabilities in neutralization and infected cell binding in a novel cohort and by defining the relationships between these parameters for a panel of bNAbs.IMPORTANCE Although antiretroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their ability to both prevent the infection of new cells (neutralization) and direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected cell binding, we observed variation both between individuals and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.

KEYWORDS:

ADCC; antibody-dependent cell cytotoxicity; bNAb; broadly neutralizing antibody; correlation; human immunodeficiency virus; infected cell binding; neutralization

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center