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

Abstract

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<super>+</super> and CD8<super> +</super> RTEs in healthy people and for CD4<super>+</super> RTEs during HIV-1 infection. Studies have indicated the thymus can be infected by HIV-1, contributing to CD4<super>+</super> 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.