Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness.
OBJECTIVE
To investigate the role of thymic output and viral fitness in immune reconstitution in HIV-1-infected children on antiretroviral therapy.


METHODS
Thymic output was studied by measuring levels of T-cell receptor rearrangement excision circles (TREC) in peripheral blood lymphocytes, using a real-time quantitative PCR assay. Recombinant viruses containing pre-therapy or post-therapy HIV-1 protease domains were evaluated for viral infectivity in a quantitative single-cycle assay.


RESULTS
Eighteen HIV-1-infected children who showed a significant increase in CD4 T-cell count after therapy were studied; HIV-1 plasma viraemia was substantially suppressed in 12 children (virological responders), but not in the other six (virological non-responders). TREC were quantified at baseline, and sequentially during the first 12 months of therapy. Both virological responders and non-responders showed an increase in TREC levels that was inversely correlated with baseline TREC and CD4 T cell counts. Changes in TREC positively correlated with CD4 T-cell count increases in virological responders, but not in non-responders; moreover, the ratios between TREC and CD4 T-cell count increases were higher in non-responders than in responders, suggesting a persistence of peripheral CD4 T-cell loss in the former. Drug-resistant viruses with reduced replicative capacity were documented in three out of six non-responders.


CONCLUSIONS
These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution, and suggest that CD4 T-cell increase despite persistent viraemia is sustained by a continuous thymic output that compensates peripheral CD4 T-cell depletion which might be slowed down by emerging viruses with reduced fitness.
Ometto
Lucia
L
Department of Oncology and Surgical Sciences, Oncology Section, AIDS Reference Center, University of Padova, Italy.
De Forni
Davide
D
Patiri
Fiorulla
F
Trouplin
Virginie
V
Mammano
Fabrizio
F
Giacomet
Vania
V
Giaquinto
Carlo
C
Douek
Daniel
D
Koup
Richard
R
De Rossi
Anita
A
D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D004279:DNA, Viral; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D013950:Thymus Gland / Q000276:immunology*; D019562:Viral Load; D014774:Virulence
D019380:Anti-HIV Agents; D017931:DNA Primers; D004279:DNA, Viral