Background. Susceptibility to coinfections in human immunodefciency virus (HIV)-infected patients remains increased
despite antiretroviral therapy (ART). To elucidate mechanisms involved in immune reconstitution, we studied immune activation,
immune exhaustion, and HIV- and copathogen-specifc T-cell responses in children before and afer ART.
Methods. We prospectively enrolled 25 HIV-infected children to study HIV-, cytomegalovirus (CMV)-, and tuberculosis (TB)-
specifc T-cell responses before and 1 year afer initiation of ART using intracellular cytokine (interleukin-2, interferon-γ, tumor
necrosis factor-α) staining assays afer in vitro stimulation. We further measured expression of activation, immune exhaustion, and
memory phenotype markers and studied proliferative responses afer antigen stimulation.
Results. We observed diferential, pathogen-specifc changes afer 1 year of ART in cytokine profles of CD4 T-cell responses
that were associated with shifs in memory phenotype and decreased programmed cell death 1 (PD-1) expression. Te proliferative
capacity of HIV- and PPD-specifc responses increased afer 1 year of ART. Of note, the recovery of CMV- and TB-specifc responses
was correlated with a decrease in PD-1 expression (r = 0.83, P = .008 and r = 0.81, P = .0007, respectively).
Conclusions. Reconstitution of immune responses on ART is associated with alterations in T-cell phenotype, function, and
PD-1 expression that are distinct for HIV, TB, and CMV. Te PD-1 pathway represents a potential target for immunotherapy in HIVinfected patients on ART with insufcient immune reconstitution
