Landscape of Human Immunodeficiency Virus Neutralization Susceptibilities Across Tissue Reservoirs.

BACKGROUND

Human immunodeficiency virus type 1 (HIV-1) sequence diversity and the presence of archived epitope muta-tions in antibody binding sites are a major obstacle for the clinical application of broadly neutralizing antibodies (bNAbs) against HIV-1. Specifically, it is unclear to what degree the viral reservoir is compartmentalized and if virus susceptibility to antibody neutralization differs across tissues.

METHODS

The Last Gift cohort enrolled 7 people with HIV diagnosed with a terminal illness and collected antemortem blood and postmortem tissues across 33 anatomical compartments for near full-length env HIV genome sequencing. Using these data, we applied a Bayesian machine-learning model (Markov chain Monte Carlo-support vector machine) that uses HIV-1 envelope sequences and approximated glycan-occupancy information to quantitatively predict the half-maximal inhib-itory concentrations (IC50) of bNAbs, allowing us to map neutralization resistance pattern across tissue reservoirs.

RESULTS

Predicted mean susceptibilities across tissues within participants were relatively homogenous, and the susceptibility pattern observed in blood often matched what was predicted for tissues. However, selected tissues, such as the brain, showed ev-idence of compartmentalized viral populations with distinct neutralization susceptibilities in some participants. Additionally, we found substantial heterogeneity in the range of neutralization susceptibilities across tissues within and between indi-viduals, and between bNAbs within individuals (standard deviation of log2(IC50) >3.4).

CONCLUSIONS

Blood-based screening methods to determine viral susceptibility to bNAbs might underestimate the presence of resistant viral variants in tissues. The extent to which these resistant viruses are clinically relevant, that is, lead to bNAb therapeutic failure, needs to be further explored.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [e-mail].

Déclaration de conflit d'intérêts

Potential conflicts of interest. B. J. reports stock or stock options in Gilead Sciences. D. M. S. reports consulting fees from Arena Pharmaceuticals, Bayer, Matrix Biomed, and Model Medicines; payment or honoraria from IAS USA, Medscape, and Kiadis; and stock or stock options from Linear Therapies (Vx Biosciences), Model Medicines, and Fluxergy. C. S. T. reports an NIH grant (MH112360) unrelated to the study. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.