Mathematical modeling of human thymic function in health and during HIV-1 infection and treatment.

摘要

The human thymus exports newly-generated T cells to the periphery which is essential for establishing and maintaining the peripheral T cell pool. Lack of a phenotypic marker to identify these human recent thymic emigrants (RTES) is the biggest hurdle towards accurately quantifying thymic output. T cell receptor excision circles (TRECs) are presently used as a measure of RTEs. To address the question whether TRECs reflect the number of RTEs or are mainly altered by peripheral T cell dynamics, we constructed a mathematical model illustrating the temporal dynamics of TREC concentration. By applying this model to aging and HIV-1 infection scenarios, we demonstrate that TREC concentration is a good measurement for CD4+ and CD8 + RTEs in healthy people and for CD4+ RTEs during HIV-1 infection.; Studies have indicated the thymus can be infected by HIV-1, contributing to CD4+ T cell decline in the periphery. The second part of thesis was to determine whether thymic infection relates to differences in HIV-1 disease progression. We developed a mathematical model describing dynamic interactions between different HIV-1 strains (R5 that uses CCR5 as coreceptor and X4 that uses CXCR4 as coreceptor) and thymocytes. Our results demonstrate that thymic infection with different HIV-1 strains induces thymic dysfunction to varying degrees, contributing to differences in disease progression. Thymic infection in children is more severe than in adults, which relates to a more active thymus and higher viral load. Treatment results indicate that with adequate suppression of viral replication in both blood and thymus, thymic reconstitution of immune cells can occur.; Three CC-chemokines, MIP-1alpha (CCL3), MIP-1beta (CCL4), and RANTES (CCL5) are natural ligands for HIV-1 coreceptor CCR5. The third part of thesis was to elucidate whether CC-chemokines correlate with HIV-1 disease progression and treatment. We performed a longitudinal study by measuring the presence of three CC-chemokines in the serum of 60 HIV-1 infected patients for 2 years. Our results demonstrate no correlations between CC-chemokines and HIV-1 disease progression. Similar levels of CC-chemokines are observed between treatment responders and non-responders. These findings suggest serum CC-chemokines likely do not contribute systemically in controlling HIV-1 disease progression and response to treatment.