Reduced Thymic Output Is a Major Mechanism of Immune Reconstitution Failure in HIV-Infected Patients After Long-term Antiretroviral Therapy

Background. Approximately 20% of human immunodeficiency virus type 1 (HIV-1)-infected adults do not normalize their CD4(+) T lymphocytes after long-term effective highly active antiretroviral therapy (HAART). The mechanistic basis for this failure is unclear. Methods. Seventy-four patients were followed up regularly for 3-7 years. Patients with undetectable plasma viral load (<50 copies/mL) for over 12 months were further classified into 2 groups: (1) immunological nonresponders, whose CD4(+) T-cell count was <200/mu L or <20% compared with baseline; and (2) immunological responders, whose CD4(+) T-cell count was >300/mu L or >30% compared with baseline. Results. Compared with 17 immunological responders, 13 immunological nonresponders had a lower magnitude of naive CD4(+) T-cell increase, a lower percentage of recent thymic immigrants (CD31(+)%), and a higher percentage of activated CD8(+) T cells. Furthermore, unlike CD4(+) T cells, which increased along with the decrease of viral load, the percentage of recent thymic immigrants (CD31(+)%) had little change in the majority of patients. These data were fit into a mathematical model, N(t)=A+B[1-exp(-t/tau)], from which we deduced that the initial rate of CD4(+) T-cell restoration is associated significantly with the percentage of recent thymic immigrants (CD31(+)%). Conclusions. Our data indicate that the failure to restore CD4(+) T-cell count following HAART was associated primarily with a defect in recent thymic immigrants, which suggests the existence of thymus exhaustion.