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ABSTRACT Several lines of evidence suggest that HIV-1 is present in the thymus during HIV-1 infection. Precursors to mature CD4+ T lymphocytes develop in the thymus, which suggests that thymic infection may play a role in the CD4+ T-cell decline observed during the course of pediatric HIV-1 infection. We illustrate, through mathematical modeling, the potential effects of thymic infection on the course of pediatric AIDS disease progression. We find that infection in the thymus not only can supplement peripheral infection but can help explain the faster progression in pediatric cases, as well as the early and high viral burden.