Maria Ines Boechat, Paige Cooper, Paul Krogstad, Pietro Lovato, Otto O. Yang, Christian R. Aguilera-Sandoval, Christina M. Ramirez, Nebojsa Jojic, Diana Y. Chen, Joseph A. Church, Marvin Belzer, and Jun Zuo
Supranormal thymic output up to 2 decades after HIV-1 infection Christian R. Aguilera-Sandoval a , Otto O. Yang a,b , Nebojsa Jojic c , Pietro Lovato d , Diana Y. Chen a , Maria Ines Boechat a , Paige Cooper a , Jun Zuo a , Christina Ramirez e , Marvin Belzer f , Joseph A. Church f and Paul Krogstad a Objectives: AIDS is caused by CD4 þ T-cell depletion. Although combination anti- retroviral therapy can restore blood T-cell numbers, the clonal diversity of the recon- stituting 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 ¼ 39) and control (n ¼ 28) participants ranging from 13 to 23 years of age. CD4 þ T cells including naive (CD27 þ CD45RA þ ) and recent thymic emigrant (RTE) (CD31 þ /CD45RA þ ) cells, were quantified by flow cytometry. Deep sequencing was used to examine T-cell receptor (TCR) sequence diversity in sorted RTE CD4 þ T cells. Results: Infected participants had reduced CD4 þ T-cell levels with predominant depletion of the memory subset and preservation of naive cells. RTE CD4 þ T-cell levels were normal in most infected individuals, and enhanced thymopoiesis was indicated by higher proportions of CD4 þ T cells containing TCR recombination excision circles. Memory CD4 þ T-cell depletion was highly associated with CD8 þ T-cell activation in HIV-1-infected persons and plasma interlekin-7 levels were corre- lated with naive CD4 þ T cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4 þ 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 þ 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. Copyright s 2016 Wolters Kluwer Health, Inc. All rights reserved. AIDS 2016, 30:701–711 Keywords: adolescents, CD4 þ T cells, immune reconstitution, perinatal HIV infection, recent thymic emigrant, T-cell receptor, thymopoiesis, T-cell receptor recombination excision circles a David Geffen School of Medicine, University of California, b AIDS Healthcare Foundation, Los Angeles, California, USA, Microsoft Corporation, d Department of Computer Science, University of Verona, Verona, Italy, e Fielding School of Public Health, University of California, and f Children’s Hospital Los Angeles and the Keck School of Medicine at University of Southern California, Los Angeles, California, USA. Correspondence to Paul Krogstad, MD, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, 615 Charles E. Young Drive South, BSRB 173, Los Angeles, CA, USA. Tel: +1 310 825 5235; fax: +1 310 206 4764; e-mail: pkrogstad@mednet.ucla.edu Received: 2 September 2015; revised: 24 November 2015; accepted: 16 December 2015. c DOI:10.1097/QAD.0000000000001010 ISSN 0269-9370 Copyright Q 2016 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.