Virus and CTL dynamics in the extrafollicular and follicular tissue compartments in SIV-infected macaques.
AffiliationUniv Arizona, Div Infect Dis
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationWodarz D, Skinner PJ, Levy DN, Connick E (2018) Virus and CTL dynamics in the extrafollicular and follicular tissue compartments in SIV-infected macaques. PLoS Comput Biol 14(10): e1006461. https://doi.org/10.1371/journal.pcbi.1006461
JournalPLOS COMPUTATIONAL BIOLOGY
Rights© 2018 Wodarz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractData from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extrafollicular compartment, with migration accounting for the presence of CTL in the follicle. In the second model, follicular CTL can also undergo antigen-induced expansion. Consistent with experimental data, both models predict increased virus compartmentalization in the presence of stronger CTL responses and lower virus loads, and a more pronounced rise of extrafollicular compared to follicular virus during CD8 cell depletion experiments. The models, however, differ in other aspects. The follicular expansion model results in dynamics that promote the clearance of productive infection in the extrafollicular site, with any productively infected cells found being the result of immigration from the follicle. This is not observed in the model without follicular CTL expansion. The models further predict different consequences of introducing engineered, follicular-homing CTL, which has been proposed as a therapeutic means to improve virus control. Without follicular CTL expansion, this is predicted to result in a reduction of virus load in both compartments. The follicular CTL expansion model, however, makes the counter-intuitive prediction that addition of F-homing CTL not only results in a reduction of follicular virus load, but also in an increase in extrafollicular virus replication. These predictions remain to be experimentally tested, which will be relevant for distinguishing between models and for understanding how therapeutic introduction of F-homing CTL might impact the overall dynamics of the infection.
NoteOpen access journal
VersionFinal published version
SponsorsNational Science Foundation [DMS 1662146/1662096]; National Institutes of Health [R01 AI096966, UM1AI126617, P51OD011106, R24 OD010976, U24 AI126683]
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