Abstract
Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation.
Highlights
HIV infection initiates a series of complex events culminating in profound immunosuppression caused by functional abnormalities and quantitative depletion of CD4+ T lymphocytes
We investigated thymopoiesis in HIV-1 infected and healthy adults by performing ex-vivo analyses on thymuses obtained from either HIV-infected or HIV-uninfected individuals
Our data indicate that HIV-infection does not impair thymopoiesis per se, but rather induces increased proliferation and activation of thymocytes which may, in the long term, cause clonal exhaustion of T cells and inflammatory damage to lymphoid tissue
Summary
HIV infection initiates a series of complex events culminating in profound immunosuppression caused by functional abnormalities and quantitative depletion of CD4+ T lymphocytes. The mechanism(s) responsible for the progressive CD4 cell count decline seen in untreated HIV infection remain a matter of controversy [1,2,3,4]. Current observations suggest that direct infection of target cells is only partially responsible for T-cell depletion. A more complex model which includes alterations in immune activation, T-cell turnover and homeostatic regulation, is favoured [5,6,7,8]. HIV infection leads to sustained immune activation and to major alterations in T cell homeostasis [9,10,11,12,13]. Naive cells, CD4 and CD8 alike, are progressively depleted, possibly as a consequence of their frequent activation and differentiation into memory cells caused by chronic and high antigenic stimulation
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