Coverage of primary mother-to-child HIV transmission isolates by second-generation broadly neutralizing antibodies

Nakamura, Kyle J.a; Cerini, Chiaraa; Sobrera, Edwin R.a; Heath, Laurab; Sinkala, Mosesc; Kankasa, Chipepod; Thea, Donald M.e; Mullins, James I.b; Kuhn, Louisef; Aldrovandi, Grace M.a

AIDS:
doi: 10.1097/QAD.0b013e32835cadd6
Basic Science
Abstract

Objectives and design: A vaccine capable of providing cross-clade, sterilizing protection has been the holy grail of HIV-1 prevention and control since the beginning of the pandemic. A major component of this effort has been the identification and characterization of broadly neutralizing antibodies (bNAbs). Recent advances in bNAb isolation, structure-based engineering, and vector-mediated gene transfer have led to increased interest in bypassing the immune system by expressing neutralizing antibodies directly in muscle. To assess the neutralization potency and coverage of a panel of second-generation bNAbs, we cloned and phenotypically characterized 227 primary HIV-1 envelopes from 23 mother-to-child transmission (MTCT) pairs.

Methods: Viral envelopes were tested for in-vitro neutralization sensitivity using a standard pseudotype assay system. A 50% inhibitory concentration (IC50) at least 10 μg/ml was used to define neutralization resistance.

Results: The combination of antibodies PG16 and NIH45–46G54W had the broadest activity with the highest neutralization potency, achieving full coverage of 87% of transmission pairs (at a median sampling depth of 10 envelopes per pair) and 96% of recently infected infants in a very conservative analysis.

Conclusions: Our data strongly support the inclusion of NIH45–46G54W, or a more extensively modified variant, in future proof-of-principle immunoprophylaxis or gene therapy-based trials. Furthermore, until robust sequence-based resistance detection becomes available, it will be necessary to conduct deeper phenotypic screening of primary isolates in order to determine the prevalence of minor resistant variants to help in selecting the best reagents for clinical trials.

Author Information

aDepartment of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California

bDepartment of Microbiology, University of Washington, Seattle, Washington USA

cLusaka District Health Management Team

dUniversity Teaching Hospital, University of Zambia, Lusaka, Zambia

eCenter for International Health and Development, Boston University School of Public Health, Boston, Massachusetts

fDepartment of Epidemiology, Columbia University, New York, New York, USA.

Correspondence to Grace M. Aldrovandi, Childrens Hospital Los Angeles, Los Angeles, USA. E-mail: galdrovandi@chla.usc.edu

Received 25 July, 2012

Revised 1 November, 2012

Accepted 15 November, 2012

© 2013 Lippincott Williams & Wilkins, Inc.