Reduced thymic output is a major mechanism of immune reconstitution failure in HIV-infected patients after long-term antiretroviral therapy

Abstract

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/μL or <20% compared with baseline; and (2) immunological responders, whose CD4 + T-cell count was >300/μL 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, 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. © 2011 The Author.