Editor: Impaired T cell function during chronic HIV infection is associated with viral persistence and sustained expression of inhibitory receptors. 1–4 We and others have previously reported that HIV-specific T cells from subjects with chronic HIV infection express high levels of the inhibitory receptor program death 1 (PD-1) and that its expression decreases with successful antiretroviral therapy (ART). 1, 2, 4, 5 Recently T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3), a membrane protein initially identified on terminally differentiated Th1 cells in mice, 6 was shown to be upregulated on virus-specific T cells from patients with chronic HIV3 and HCV infection. 7 In light of these findings, we assessed the expression of TIM-3 on HIV-specific CD8+ T cells in subjects with treated and untreated chronic HIV infection. Our findings demonstrate that (1) HIV-specific CD8+ T cells from subjects receiving successful ART expressed significantly lower levels of TIM-3 compared with those from viremic subjects,(2) there was a positive correlation between TIM-3 expression on HIV-specific CD8+ T cells and HIV plasma viral load,(3) expression of TIM-3 was significantly higher in HIV-specific CD4+ T cells than in HIV-specific CD8+ T cells, and (4) TIM-3 expression in HIV-specific CD8+ T cells correlated directly with its expression on HIV-specific CD4+ T cells from the same subjects. These findings indicate that there is an association between suppression of HIV viremia by ART and decreased expression of TIM-3, suggesting that HIV replication increases the expression of this receptor during chronic infection, which further impairs CD8+ T cell function. Forty-three chronically HIV-1-infected subjects with progressive disease were enrolled into two clinical cohorts based on their treatment status: on ART with virological suppression (suppressed) and untreated (viremic). Suppressed subjects (n= 18) included those receiving a combination of antiretroviral agents with suppression of plasma viral load to< 48 copies of HIV-1 RNA per ml of plasma for 6 month (median CD4+ T cell count, 574 cells/μl; range, 396–2444 cells/μl). Viremic subjects (n= 25) were either treatment naive or off treatment for 6 months with a median viral load of 16,200 copies HIV-1 RNA per ml of plasma (range, 223–179,000 copies of HIV RNA per ml) and a median CD4+ T cell count of 464 cells/μl (range, 306–840 cells/μl). All study subjects participated voluntarily and gave informed consent.

The study was approved by the University of Colorado Denver Institutional Review Board. Blood collection, peripheral blood mononuclear cell (PBMC) isolation, T cell stimulation for HIV-1 Gag-specific cytokine production, immunofluorescent staining of stimulated T cells, and multiparametric flow cytometry were performed following a previously published procedure. 2 Statistical analysis was performed using GraphPad Prism. The Mann–Whitney test and Wilcoxon signed rank test were utilized to determine significance of differences between groups. Correlations were calculated using the nonparametric Spearman test. P-values of< 0.05 were considered statistically significant. Figure 1A is a representative histogram of TIM-3 expression on HIV-specific interferon (IFN)-у-producing CD8+ T cells from a viremic and suppressed subject with chronic HIV infection. As shown in Fig. 1B, the percentage TIM-3 expressing HIV-specific IFN-у-producing CD8+ T cells was significantly lower in suppressed subjects (median, range; 8%, 1–9%) than in viremic subjects (21%, 2–68%, p= 0.003, Fig. 1B). In line with this finding, a recent study demonstrated a decline in TIM-3 expression in total CD4+ and CD8+ T cells …