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Abstract In the secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate both in the follicular and the extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTL home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counterintuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in SIV-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity, and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo.
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This content will become publicly available on February 1, 2026
Compartmental structure in the secondary lymphoid tissue can slow down in vivo HIV-1 evolution in the presence of strong CTL responses
Human immunodeficiency virus (HIV-1) replicates in the secondary lymphoid tissues, which are characterized by complex compartmental structures. While cytotoxic T lymphocytes (CTL) readily access infected cells in the extrafollicular compartments, they do not home to follicular compartments, which thus represent an immune-privileged site. Using mathematical models, previous work has shown that this compartmental tissue structure can delay the emergence of CTL escape mutants. Here, we show computationally that the compartmental structure can have an impact on the evolution of advantageous mutants that are not related to CTL recognition: (i) compartmental structure can influence the fixation probability of an advantageous mutant, with weakened selection occurring if CTL responses are of intermediate strength; (ii) compartmental structure is predicted to reduce the rate of mutant generation, which becomes more pronounced for stronger CTL responses; and (iii) compartmental structure is predicted to slow down the overall rate of mutant invasion, with the effect becoming more pronounced for stronger CTL responses. Altogether, this work shows thatin vivovirus evolution proceeds slower in models with compartmental structure compared with models that assume equivalent virus load in the absence of compartmental structure, especially for strong CTL-mediated virus control. This has implications for understanding the rate of disease progression.
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- PAR ID:
- 10614384
- Publisher / Repository:
- The Royal Society
- Date Published:
- Journal Name:
- Journal of The Royal Society Interface
- Volume:
- 22
- Issue:
- 223
- ISSN:
- 1742-5662
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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