Thymic function in HIV-infection.

This thesis is based on seven previously published articles. The work was performed during my employment at The Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, as a scholarship student from 2000-2001 and as a research assistant in the period 2004-2010. HIV-infection is characterized by CD4+ cell depletion. The differences between patients in the degree of CD4+ cell recovery upon treatment with highly active antiretroviral therapy (HAART) may in part be due to differences in the supply of naïve CD4+ cells from the thymus. The thymus atrophies with increasing age for which reason the adult thymus was previously assumed to be without function. The aim of these investigations was to examine the role of the thymus in different aspects of HIV-infection: In adult HIV-infected patients, during HIV-positive pregnancy, and in HIV-exposed uninfected (HIV-EU) children born to HIV-infected mothers. Thymic size and output were determined in 25 adult HIV-infected patients receiving HAART and in 10 controls. Larger thymic size was associated with higher CD4 counts and higher thymic output. Furthermore, patients with abundant thymic tissue seemed to have broader immunological repertoires, compared with patients with minimal thymic tissue. The study supports the mounting evidence of a contribution by the adult thymus to immune reconstitution in HIV-infection. In a follow-up study conducted till 5 years of HAART, the importance of the thymus to the rate of cellular restoration was found to primarily lie within the first two years of HAART. The effect of recombinant human growth hormone (rhGH) was then investigated in a randomized, double-blinded placebo controlled trial in 46 adult HIV-infected patients on HAART. Daily treatment with a low dose of rhGH of 0.7mg for 40 weeks stimulated thymopoiesis as expressed by thymic size, density, and output strongly supporting the assumption that rhGH possesses the potential to stimulate the ageing thymus, holding promise as a future means to complete CD4 restoration and renew the TCR repertoire in patients who respond insufficiently to HAART. Apart from naïve T cells, regulatory T cells (Tregs) are developed in the thymus. Tregs play a critical role in peripheral tolerance and suppress inappropriate immune activation such as induced by HIV. We studied levels of Tregs in adult HIV-infected patients with known thymic output. Our studies demonstrate increased levels of Tregs in HIV-infected patients despite long-term treatment with HAART, suppressed viral loads, and normalized CD4 counts and immune activation suggesting that Tregs expand irreversibly in HIV-infection independently of viral load, CD4 depletion or level of immune activation. Our data further suggest that elevated levels of Tregs in HIV-infected adults may in part be due to increased thymic production of naive Tregs. During pregnancy, establishing fetal-maternal tolerance is essential to pregnancy success. In a prospective study on HIV-positive and HIV-negative pregnant women we found alterations in thymic output and Treg levels in HIV-negative pregnant women compatible with such an establishment. HIV-infected women, however, displayed different immunological profiles from HIV-negative women, and this immune unbalance may interfere with the prevention of fetal rejection and may partly explain the increased risk of abortion in HIV-infected women. We finally examined thymic function in 20 HIV-EU children at 15 months of age. The thymus was reduced in size in HIV-EU children compared with children born to HIV-negative mothers, but no evidence of impaired thymic function, immune regulation, or antibody vaccination response was detected, suggesting that no qualitative immune deficits persist in HIV-EU children beyond infancy. In conclusion, the thymus is functional in adults, and it contributes to immunological recovery in HIV-infected patients primarily during the first two years of HAART. Treg levels are increased in HIV-infected patients independent of viral load, CD4 cell depletion or level of immune activation, and this may be due to increased thymic production of naïve Tregs. Alteration of thymic function in adults is possible, both by stimulation of thymopoiesis with rhGH therapy and as a result of pregnancy. Finally, immunological abnormalities detected in HIV-EU infants are recovered at 15 months of age, and even if diminished in size, thymic function is normalized at this age.