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TO THE EDITOR—Wilson et al [1] demonstrated that, in human immunodeficiency virus (HIV)–infected subjects, levels of inflammatory biomarkers known to be associated with increased clinical risk (interleukin 6, D-dimer, high sensitive reactive-C protein, soluble CD14, and soluble CD163) are more closely related to markers of monocyte activation and migration than to markers of T-cell activation. These data suggest that monocytes may play a prominent role in chronic and serious non-AIDS events, such as premature cardiovascular disease and cancer. Meanwhile, several large cohort studies have demonstrated that HIVinfected subjects who do not undergo full CD4 T-cell restoration during antiretroviral therapy (ART) (ie, those with immune failure [IF]) are at greater risk of developing these non-AIDS conditions [2–6]. Based on the findings of Wilson et al [1], we investigated monocyte activation phenotypes in a group of patients with IF, compared with patients who did obtain full CD4 T-cell recovery with therapy (immune success [IS]). We performed a cross-sectional study in 84 HIV-infected subjects with current CD4 T-cell counts <350/μL (IF; n = 39) or >500/μL (IS; n = 45) after ≥18 months of ART and with HIV RNA levels <50 copies/mL for≥12 months. Peripheral monocyte/macrophage (M/M) phenotypes (based on CD14 and CD16 surface expression in classic CD14CD16, intermediate CD14CD16, and nonclassic CD14CD16 monocytes) as well as specific surface activation markers (eg, CD163 and CD11b) were evaluated by flow cytometry on fresh samples. Patient demographic characteristics and immunological findings are provided in Table 1. The 2 groups were matched by both age and CD4 T-cell nadir. The IF and IS patient groups did not significantly differ by sex, duration of HIV infection, modality of transmission for HIV infection, Centers for Disease Control and Prevention stage, length of ART, or hepatitis B virus infection. The prevalence of hepatitis C virus infection was higher in patients with IF than in those with IS (38.5% vs 17.8%, respectively; P < .05). By definition, patients with IF displayed lower CD4 T-cell counts (median [interquartile range (IQR)] for IF vs IS, 268 [218–314] vs 663 [550–850] cells/μL; P < .05). A developmental relationship between circulating monocyte subsets (from classic by intermediate to nonclassic) might be postulated. During systemic infection and under proinflammatory stimuli, there is an increase first of the intermediate cells followed by the nonclassic CD14CD16 monocytes [7]. We found that, compared with patients with IS, those with IF showed lower levels of classic and higher levels of intermediate monocytes (CD14CD16, 82.5% of total CD14 [IQR, 77.0%–86.5%] for IF vs 84.5% [79.8%–88.3%] for IS [P = .05]; CD14CD16, 4.6% of total CD14 [3.2%– 6.2%] vs 4.0% [2.5%–5.1%] [P= .04]). Proportions of nonclassic monocytes were also higher in patients with IF, although this difference did not reach statistical significance (CD14CD16, 6.7% of total CD14 [4.5%–9.6%] for IF vs 5.6% [3.3%–9.0%] for IS). CD163 is a haptoglobin-hemoglobin scavenger receptor expressed by monocytes and macrophages, cleaved from the cell by proinflammatory stimuli and involved as soluble receptor (soluble CD163) in the regulation of inflammation [8]. Patients with IF displayed lower expression of CD163 than those with IS, for both total and classic monocytes (CD14CD163, 89.1% of total CD14 [IQR, 85.8%– 91.9%] for IF vs 92.5% [88.3%–93.8%] for IS [P = .02]; CD14CD16CD163, 79.9% of CD14CD16 [74.0%–83.2%] vs 83.7% [78.9%–86.9%] [P= .01]). Although the values were higher in patients with IF, we found no significant differences between the 2 groups in the proportions of CD14CD16CD163 (4.3% of CD14 CD16 [IQR, 3.0%–6.2%] for IF vs 3.9% [2.5%–5.1%] for IS; P = .07) or CD14 CD16CD163 monocytes (1.9% of CD14CD16 [0.9%–2.6%] vs 1.2% [0.6%–2.5%]; P = .35). CD11b (Mac-1), a member of the β2integrin family, is involved in monocyte adhesion and endothelial transmigration as well as in macrophage activation. Constitutively present at low levels on the cell surface, its expression is increased after proinflammatory stimulation with cytokines (interleukin 1, tumor necrosis factor, and interferon γ) and lipopolysaccharide [9]. The frequency of CD14 CD11b did not differ substantially between the 2 groups (median, 98.1% of total CD14 [IQR, 96.8%–99.1%] for IF vs 97.8% [95.8%–98.8%] for IS; P = .40]). In contrast, patients with IF showed lower proportions of CD14CD16CD11b (82.5% of CD14CD16 [IQR, 77.0%– 86.5%] for IF vs 84.5% [79.8%–88.3%] for IS; P < .05) and higher proportions of CD14CD16CD11b (4.6% of CD14 CD16 [3.2%–6.2%] vs 4.0% [2.5%– 5.1%]; P < .05) monocytes. Levels of nonclassic CD14CD16monocytes expressing CD11b did not differ significantly between the 2 groups (6.2% of CD14CD16 [IQR, 4.3%–8.9%] for IF vs 4.3% [2.9%–8.1%] for IS; P = .08). Moreover, we found no differences in the expression of HLA-DR,

Characterization of Immune Failure by Monocyte Activation Phenotypes in HIV-Infected Patients Receiving Antiretroviral Therapy: Table 1.