Background.  Failure to normalize CD4⁺ T-cell numbers despite effective antiretroviral therapy is an important problem in human immunodeficiency virus (HIV) infection.

Methods.  To evaluate potential determinants of immune failure in this setting, we performed a comprehensive immunophenotypic characterization of patients with immune failure despite HIV suppression, persons who experienced CD4⁺ T-cell restoration with therapy, and healthy controls.

Results.  Profound depletion of all CD4⁺ T-cell maturation subsets and depletion of naive CD8⁺ T cells was found in immune failure, implying failure of T-cell production/expansion. In immune failure, both CD4⁺ and CD8⁺ cells were activated but only memory CD4⁺ cells were cycling at increased frequency. This may be the consequence of inflammation induced by in vivo exposure to microbial products, as soluble levels of the endotoxin receptor CD14⁺ and interleukin 6 were elevated in immune failure. In multivariate analyses, naive T-cell depletion, phenotypic activation (CD38⁺ and HLA-DR expression), cycling of memory CD4⁺ T cells, and levels of soluble CD14 (sCD14) distinguished immune failure from immune success, even when adjusted for CD4⁺ T-cell nadir, age at treatment initiation, and other clinical indices.

Conclusions.  Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.