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* Department of Immunology, University Medical Center, Utrecht, The Netherlands and Sanquin Research and Academic Medical Center, Amsterdam, The Netherlands;
Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands;
Division of Infectious Diseases, Tropical Medicine and AIDS, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands;
International Antiviral Therapy Evaluation Center, Amsterdam, The Netherlands;
¶ Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
|| Department of Paediatric Infectious Diseases, University Medical Center, Utrecht, The Netherlands;
# Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada; and
** Theoretical Biology, Utrecht University, Utrecht, The Netherlands
It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/µl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4–9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/µl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by AIDS Fonds Netherlands (Grant 7010), the WKZ Fund, and the Netherlands Organization for Scientific Research (916.36.003 and 016.048.603). This work is part of the Amsterdam Cohort Studies on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, and the University Medical Center Utrecht, part of the Netherlands HIV Monitoring Foundation, which is financially supported by The Netherlands National Institute for Public Health and the Environment.
2 N.V. and R.v.G. contributed equally.
3 Address correspondence and reprint requests to Dr. Frank Miedema, Department of Immunology, University Medical Center, Lundlaan 6, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail address: F.Miedema{at}umcutrecht.nl
4 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; TREC, TCR excision circle; SCT, stem cell transplantation.
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