Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function

Objective: To characterize immune phenotype and thymic function in HIV-1-infected adults with excellent virologic and poor immunologic responses to highly active antiretroviral therapy (HAART). Methods: Cross-sectional study of patients with CD4 T cell rises of ≥200×10⁶ cells/ I (CD4 responders; n=10) or <100×10⁶ cells/I (poor responders; n=12) in the first year of therapy. Results: Poor responders were older than CD4 responders (46 versus 38 years; P<0.01) and, before HAART, had higher CD4 cell counts (170 versus 35×10⁶ cells/ I; P=0.11) and CD8 cell counts (780 versus 536×10⁶ cells/I; P=0.02). After a median of 160 weeks of therapy, CD4 responders had more circulating naive phenotype (CD45+CD62L+) CD4 cells (227 versus 44×10⁶ cells/I; P=0.001) and naive phenotype CD8 cells (487 versus 174×10⁶ cells/I; P=0.004) than did poor responders (after 130 weeks). Computed tomographic scans showed minimal thymic tissue in 11/12 poor responders and abundant tissue in 7/10 responders (P=0.006). Poor responders had fewer CD4 cells containing T cell receptor excision circles (TREC) compared with CD4 responders (2.12 versus 27.5×10⁶ cells/I; P=0.004) and had shorter telomeres in CD4 cells (3.8 versus 5.3 kb; P=0.05). Metabolic labeling studies with deuterated glucose indicated that the lower frequency of TREC-containing lymphocytes in poor responders was not caused by accelerated proliferation kinetics. Conclusion: Poor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.