Thymic Function Failure Is Associated With Human Immunodeficiency Virus Disease Progression.
Thymic function has been mainly analyzed with surrogate peripheral markers affected by peripheral T-cell expansion, making it difficult to assess the role of thymic failure in human immunodeficiency virus (HIV) disease progression. The assay of signal-joint/DβJβ T-cell rearrangement excision circles (sj/β-TREC ratio) overcomes this limitation but has only been assayed in small cohorts. Thus, the aim of this study was to determine the role of thymic function, measured by the sj/β-TREC ratio, on CD4 T-cell maintenance in prospective HIV cohorts that include patients with a wide age range and different immunological phenotypes.



Seven hundred seventy-four patients including typical progressors, long-term nonprogressors (LTNPs), and vertically HIV-infected subjects were analyzed. Thymic function was quantified in peripheral blood samples using the sj/β-TREC ratio. Associations between thymic function and CD4 T-cell dynamics and combination antiretroviral therapy (cART) onset were analyzed using linear, logistic, and Cox proportional hazard models.



Thymic function failure (sj/β-TREC ratio <10) was independently associated with HIV progression. In agreement, patients with distinctive high CD4 T-cell levels and low progression rates (vertically HIV-infected patients and LTNPs, including HIV controllers) had significantly higher thymic function levels whereas patients with thymic function failure had lower CD4 T-cell levels, lower nadir, and faster CD4 T-cell decay.



This work establishes the relevance of thymic function, measured by sj/β-TREC ratio, in HIV disease progression by analyzing a large number of patients in 3 cohorts with different HIV disease progression phenotypes. These results support and help to understand the mechanisms underlying the rationale of early cART onset.
Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Sara
S
Ferrando-Martinez
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Rebeca S
RS
De Pablo-Bernal
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Marta
M
De Luna-Romero
Molecular Immunobiology Laboratory, General University Hospital Gregorio Marañon, Health Research Institute Gregorio Marañon, Spanish HIV HGM BioBank, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Madrid, Spain.
Santiago J
SJ
De Ory
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Miguel
M
Genebat
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Yolanda M
YM
Pacheco
Infectious Disease Unit, General Universitary Hospital Gregorio Marañon, Madrid, Spain.
Francisco J
FJ
Parras
Infectious Disease Unit, Polytechnic and University Hospital La Fe, Valencia, Spain.
Marta
M
Montero
Infectious Diseases Department, Hospital San Pedro, Center for Biomedical Research of La Rioja, Logrono, Spain.
Jose Ramón
JR
Blanco
Hospital General de Elche and Universidad Miguel Hernández, Alicante, Spain.
Felix
F
Gutierrez
Infectious Diseases Unit, Virgen de la Victoria University Hospital, Instituto de Investigación Biomédica de Málaga, Spain.
Jesus
J
Santos
Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Spain.
Francisco
F
Vidal
Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Richard A
RA
Koup
Molecular Immunobiology Laboratory, General University Hospital Gregorio Marañon, Health Research Institute Gregorio Marañon, Spanish HIV HGM BioBank, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Madrid, Spain.
María Ángeles
MÁ
Muñoz-Fernández
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Manuel
M
Leal
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Ezequiel
E
Ruiz-Mateos
D000293:Adolescent; D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013950:Thymus Gland / Q000473:pathology*; D055815:Young Adult
D044966:Anti-Retroviral Agents; D015415:Biomarkers
HIV disease progression; LTNP; sj/β-TREC ratio; thymic function; vertical infection