Supranormal thymic output up to 2 decades after HIV-1 infection


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Abstract

Objectives:AIDS is caused by CD4+ T-cell depletion. Although combination antiretroviral therapy can restore blood T-cell numbers, the clonal diversity of the reconstituting cells, critical for immunocompetence, is not well defined.Methods:We performed an extensive analysis of parameters of thymic function in perinatally HIV-1-infected (n = 39) and control (n = 28) participants ranging from 13 to 23 years of age. CD4+ T cells including naive (CD27+ CD45RA+) and recent thymic emigrant (RTE) (CD31+/CD45RA+) cells, were quantified by flow cytometry. Deep sequencing was used to examine T-cell receptor (TCR) sequence diversity in sorted RTE CD4+ T cells.Results:Infected participants had reduced CD4+ T-cell levels with predominant depletion of the memory subset and preservation of naive cells. RTE CD4+ T-cell levels were normal in most infected individuals, and enhanced thymopoiesis was indicated by higher proportions of CD4+ T cells containing TCR recombination excision circles. Memory CD4+ T-cell depletion was highly associated with CD8+ T-cell activation in HIV-1-infected persons and plasma interlekin-7 levels were correlated with naive CD4+ T cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4+ T-cell receptor sequences in well compensated infected persons demonstrated supranormal diversity, providing additional evidence of enhanced thymic output.Conclusion:Despite up to two decades of infection, many individuals have remarkable thymic reserve to compensate for ongoing CD4+ T-cell loss, although there is ongoing viral replication and immune activation despite combination antiretroviral therapy. The longer term sustainability of this physiology remains to be determined.

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