T-cell dynamics in healthy and HIV-infected individuals

Abstract

This thesis focuses on T-cell dynamics in healthy and both treated and untreated HIV-infected individuals. Although the progressive decline in CD4+ T-cell numbers is the hallmark of HIV infection, the mechanisms behind this depletion remain controversial. Currently the most prevailing ideas include direct HIV-induced cytopathicity, thymic impairment and chronic immune activation. We show that direct virus kill is insufficient to fully explain CD4+ T-cell depletion and that chronic immune activation plays a predominant role in CD4+ T-cell loss. To investigate the effects of non-HIV related chronic immune activation, we studied healthy Ethiopians who are known to have increased exposure to environmental pathogens. While immune characteristics of Ethiopian and Dutch neonates are similar, and therefore differences are not genetic, the CD4+ TREC content and fraction naive CD4+ T cells decrease at very early childhood in Ethiopia. We surprisingly found that when Dutch and Ethiopian HIV-infected patients were matched for CD4+ T-cell count, the percentages proliferating CD4+ and CD8+ T cells were lower in Ethiopians. This is in line with the slower CD4+ T-cell decline found in HIV+ Ethiopians compared to Dutch HIV-infected individuals. In chickens and mice it has been shown that recent thymic emigrants (RTE) form a substantial pool of short-lived naive T cells. In humans however, the lifespan and number of RTE are unknown. Currently there is no unambiguous marker for RTE and therefore the contribution of the thymus to the maintenance of the T-cell pool during aging, the role of thymic impairment in HIV-related CD4+ T-cell depletion and the role of thymic output during reconstitution following HAART are difficult to assess. By using in vivo heavy water labeling of T cells from young healthy adults, we determined the production of naive and memory CD4+ and CD8+ T cells, and followed the survival of these recently produced T cells. The average life-span of naive CD4+ en CD8+ T cells is 4.2 and 6.6 years and of memory CD4+ en CD8+ T cells 0.4 en 0.7 years. Furthermore, we show that in humans, recently produced naive T cells are long-lived and even preferentially incorporated into the naive T-cell pool. Our data thereby provide the first conclusive experimental evidence that there is no substantial population of short-lived RTE in healthy humans. Although children could recover to normal levels within 1 year after treatment even when HAART was initiated at an extremely lymphopenic stage, adults with a CD4+ nadir below 200 cells/l persistently sustained lower CD4+ T-cell counts than adults with high pre-therapy CD4+ T-cell counts throughout follow-up, but nevertheless normalized CD4+ T-cell counts after 7 years of HAART. Absolute numbers of naive CD4+ T cells normalized in all children and in adults with high baseline CD4+ T-cell counts, whereas naive CD4+ T-cell counts in adults with low CD4+ nadirs lagged behind. The reconstitution of the peripheral T-cell pool of adults and children was attributed to both thymic output and peripheral T-cell proliferation and did not seem to cause more 'proliferative history' of the T-cell pool as compared to age-matched controls.