Association Between HIV-1 Coreceptor Usage and Resistance to Broadly Neutralizing Antibodies

Pfeifer, Nico Dr*; Walter, Hauke MD; Lengauer, Thomas Dr, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0000000000000283
Basic and Translational Science
Abstract

Background: Recently discovered broadly neutralizing antibodies have revitalized hopes of developing a universal vaccine against HIV-1. Mainly responsible for new infections are variants only using CCR5 for cell entry, whereas CXCR4-using variants can become dominant in later infection stages.

Methods: We performed a statistical analysis on two different previously published data sets. The first data set was a panel of 199 diverse HIV-1 isolates for which IC50 neutralization titers were determined for the broadly neutralizing antibodies VRC01, VRC-PG04, PG9, and PG16. The second data set contained env sequences of viral variants extracted from HIV-1–infected humanized mice treated with the antibody PGT128 and from untreated control mice.

Results: For the panel of 199 diverse HIV-1 isolates, we found a statistically significant association between viral resistance to PG9 and PG16 and CXCR4 coreceptor usage (P = 0.0011 and P = 0.0010, respectively). Our analysis of viral variants from HIV-1–infected humanized mice under treatment with the broadly neutralizing antibody PGT128 indicated that certain antibodies might drive a viral population toward developing CXCR4 coreceptor usage capability (P = 0.0011 for the comparison between PGT128 and control measurement).

Conclusions: These analyses highlight the importance of accounting for a possible coreceptor usage bias pertaining to the effectiveness of an HIV vaccine and to passive antibody transfer as therapeutic approach.

Author Information

*Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany; and

MVZ Medizinisches Infektiologiezentrum Berlin, Berlin, Germany.

Correspondence to: Nico Pfeifer, Dr. rer. nat., Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Campus E1 4, D-66123 Saarbruecken, Germany (e-mail: nico.pfeifer@mpi-inf.mpg.de).

Supported by the BMBF project HIV Cell Entry, grant no. 0315480A. N.P. was an employee of Microsoft until 8/2011. The Max Planck Institute for Informatics collaborates with a company in the area of medical diagnostics on the topic of viral tropism of HIV. In its context, a version-controlled implementation of geno2pheno[coreceptor] with secure access is maintained by Max Planck Institute for Informatics under a paid service agreement.

N.P. designed the study, performed the experiments and interpreted the results. T.L. contributed ideas to the design and interpretation of the study. H.W. contributed ideas to the interpretation of the study. N.P., H.W., and T.L. wrote and approved the manuscript.

The authors have no further conflicts of interest to disclose.

Part of the data was presented at the AIDS Vaccine Conference 2013, October 7-10, 2013, Barcelona, Spain.

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Received March 14, 2014

Accepted June 18, 2014

© 2014 by Lippincott Williams & Wilkins