Background:  Failure to “normalize” circulating CD4 T cells despite virologic control is seen in up to 25% of ARV treated patients and is associated with increased morbidity. The determinants of immune failure in this setting are incompletely understood.

Methods:  We compared clinical and immunologic characteristics of 61 immune failure (IF) patients (CD4 < 350/uL despite >2 years of suppressive ARV therapy) to clinical characteristics of 188 immune success (IS) patients (CD4 > 500/uL within 2 yrs of ARV therapy) with detailed immunologic analyses on all immune failure patients and a subset of 20 IS subjects and 21 healthy controls.  

Results:  Immune failure patients were older at HAART start (41 vs 37 years, P <0.02), were more often male (82 vs 70%, P <0.03), and had lower CD4 nadirs (42 vs 199/uL, p <0.001) than IS patients. In multivariate analysis, only nadir CD4 was independently associated with immune failure (P <0.001). While absolute numbers of CD4 T cell maturation subsets were normal in IS patients, all subsets (naïve (N), central memory (CM), effector memory (EM)) were fewer in immune failure patients than in IS patients and in controls (P < 0.001). CD8 T cells were also lower in immune failure patients (610 cells/uL) than in IS patients (820 cells/uL, P <0.04) with differences most dramatic in the naïve CD8 T cell subset (67 vs 157/uL, P <0.001). Both CD4 and CD8 T cells were more frequently activated (CD38⁺/HLA-DR⁺) in immune failure patients (12% and 28%) than in immune success patients (6% and 19%, P <0.001) and controls (6% and 14%, P <0.001). Immune failure CD4 T cells were more frequently in cell cycle (Ki-67⁺) than were cells of immune success patients or controls (3.6% vs 2.2% and 1.9%, P <0.001) and cycling CD4 T cells were most frequently CM (4.6%) and EM cells (4.7%). In contrast, despite greater frequencies of activated CD8 T cells, cycling CD8 T cells in immune failure patients (1.5%) were not more frequent than in immune success patients (1.1%) or controls (1.0%).

Conclusions:  Immune failure after >2 years of suppressive ARV therapy immune success associated with lower CD4 nadir and, in univariate analysis, is more common in older subjects and men. Diminished numbers of both CD4 and CD8 T cells distinguish immune failure from immune success. Immune activation of CD4 and CD8 T cells is characteristic of immune failure, yet increased cycling is seen only in CM and EM CD4 cells and not among naïve CD4 cells or CD8 T cells. Immune failure in treated HIV infection may be in part related to a failure of total T cell production and is also linked to immune activation, turnover and death of memory CD4 T cells.