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Landscape of HIV neutralization susceptibilities across tissue reservoirs.

BACKGROUND
HIV-1 sequence diversity and the presence of archived epitope mutations 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 more importantly 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 new Bayesian machine-learning model (MCMC-SVM) that uses HIV-1 envelope sequences and approximated glycan-occupancy information as variables to quantitatively predict the half-maximal-inhibitory concentrations (IC50) of bNAbs. This allowed us to map the landscape of neutralization resistance across each person's tissue reservoirs.


RESULTS
Predicted mean susceptibilities across tissues within a participant were relatively homogenous and the susceptibility pattern observed in blood often matched what was predicted for tissues. Selected tissues, like the brain, however, showed in some participants evidence of compartmentalized viral populations with distinct neutralization susceptibilities. Additionally, we found substantial heterogeneity of the range of neutralization susceptibilities across tissues even within an individual, between individuals and also between bNAbs within the same individual (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. To what extent these resistant viruses are clinically relevant, ie. leading to bNAb therapeutic failure, needs to be further explored.