Background:  Although CD4⁺ and CD8⁺ lymphocytes have been widely studied in the context of structured therapy interruption in chronic HIV-1 infection, few data evaluating the natural killer (NK) cell profile in this situation are available.

Methods:  Changes in NK cell percentages measured as CD3^–CD56⁺ cells, CD3^–CD56⁺CD16⁺, CD3^–CD56⁺CD16^–, and CD3^–CD56^–CD16⁺ cells and NK-associated receptors (killer immunoglobulin-like receptors (KIR) and lectin-like receptor) were analyzed in 120 HIV-1-infected patients who underwent various structured therapy interruption regimens for 2 years or continuous HAART. Patients on HAART with CD4⁺ >450 and viral load <200 copies/mL were randomized in 3 arms according to the criteria employed to resume HAART during structured therapy interruption:  virological arm (VA, n = 45, viral load >30,000 copies/mL), immunological arm (IA, n = 38, CD4< 350 mL), and a control arm (n = 37) in which HAART was permanently maintained.

Results:  At baseline, HIV-1-infected patients had a median of CD4⁺ T cell count of 695/mm³. The median time off HAART during the 24 months of study period was significantly higher in IA than in VA (24 vs 18 months, p =  0.02). A consistent decrease in CD3^–CD56⁺ cell percentages in both VA and IA patients, but not in CA patients was observed. This decrease was especially significant in the CD3^–CD56⁺CD16⁺ subset, while the change of CD3^–CD56⁺CD16^– subset was similar between the 3 groups during the study period. The CD3^–CD56^–CD16⁺ cell subset showed an increase in the VA and IA and a drop in CA (median change 2.5%, 0.43%, and –4.9%, p = 0.05). Those patients with higher decrease in CD3^–CD56⁺CD16⁺ and CD3^–CD56⁺ cells during the study period had a higher decrease in CD4⁺ T cells (r = 0.37, p = 0.001 and r = 0.35, p = 0.001, respectively) and higher increase in plasma viral load (r = –0.24, p = 0.03 and r = –0.26, p = 0.02, respectively). KIR and lectin-like receptors expression trend to increase in CA, and decreased in the other 2 arms (more in IA than in VA). Patients who displayed a greater drop in CD3⁺CD4⁺ T cells and a greater rise in plasma viral load had a significantly higher drop in KIR and lectin-like receptors as well as in the NKG2A receptor expressed both in CD3^–C56⁺ and CD3^–CD16⁺ cells.

Conclusions:  The results indicate that patients who presented the lowest levels of total NK cells and of NK cells with a predominantly inhibitory phenotype after structured therapy interruption procedure showed the poorest virology and immunology outcomes. This finding suggests that structured therapy interruption could decrease NK subsets and phenotype in certain patients and it is related with their worst clinical evolution.