Background. We have attempted to identify factors associated with T cell reconstitution in response to highly active antiretroviral therapy.

Methods. In a prospective, multicenter cohort study, we compared clinical, immune, and viral responses to an initial antiretroviral regimen in older (⩾45 years old) versus younger (18–30 years old) human immunodeficiency virus type 1–infected subjects. Multivariable linear‐regression models identified independent factors associated with changes in T cell counts.

Results. Older subjects had smaller increases in naive T cells but greater T cell receptor–excision circle DNA content after 48 weeks, despite similar virologic responses and comparable reductions in immune activation. Changes in T cell counts were associated with plasma interleukin (IL)–7 levels in subjects with low thymic scores, whereas first‐phase T cell increases (perhaps mediated by redistribution to the circulation of tissue‐associated lymphocytes) were associated with reductions in immune activation in subjects with high thymic scores. Reductions in immune activation were associated with reductions in spontaneous lymphocyte apoptosis.

Conclusions. Distinct processes may underlie T cell restoration, according to estimated thymic volumes. IL‐7–mediated peripheral expansion may drive T cell restoration in persons with low thymic volume, whereas therapy‐associated reversal of immune reactivation may drive T cell losses and their restoration in persons with larger thymic volume.