Analysis of HIV-1 infection in the thymus

Human Immunodeficiency Virus type 1 (HIV-1) infection is dependent on the expression of CD4 and either CCR5 or CXCR4 on the target cell. T cells are a prominent reservoir for HIV-1 replication. As the source of naïve T cells in the periphery, the thymus is a critical organ for supplying the body with functional naïve T cells. Thus, understanding HIV-1 infection in the thymus would contribute to the overall understanding of HIV-1 pathogenesis in the peripheral T cell pool.; Analysis of HIV-1 infection in the thymus is performed primarily in the SCID-hu mouse model where human fetal thymus and liver pieces implanted in the SCID-hu mouse form a conjoint organ carrying out normal thymopoiesis. Additional tests are performed in thymocyte suspension cultures.; The first chapter we show that rare cell populations in the thymus are infected by HIV-1. Plasmacytoid dendritic cells (pDC) express CD4 and the coreceptors CCR5 and CXCR4. Both CXCR4 utilizing HIV-1 (X4 HIV-1) and CCR5 utilizing HIV-1 (R5 HIV-1) infect pDC, but only X4 HIV-1 is expressed in vivo. The R5 HIV-1 replication block in pDC is at the level of reverse transcription. TCRγδ thymocytes express both R5 and X4 HIV-1 in vivo. The Natural Killer cell receptor protein I expressing thymocyte population (CD 161+CD3+) lose CD4 cells coincident with CD4 cell loss in the total populations, but express considerably less virus than the conventional CD3+ thymocytes in the CD4− populations.; The second chapter analyzes HIV-1 replication throughout various steps of the viral life cycle in distinct developmental stages. The basis for this investigation is due to the dependence of HIV-1 replication on the activation state of the host cell. Since, thymopoiesis is a dynamic process, certain developmental stages may potentially be more optimal for virus replication than other stages. We find no restriction for both X4 and R5 HIV-1 at the steps of entry, reverse transcription, and nuclear import in five different thymocyte developmental stages tested. However, the differential replication kinetics and tropism between R5 and X4 HIV-1 in the thymus in vivo and in vitro is due to the differential levels of the appropriate coreceptor expression.