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TO THE EDITOR—We have read with great interest the recent articles by Tenorio et al and Hunt et al that investigated inflammation, coagulation, and T-cell activation as predictors of clinical outcome in human immunodeficiency virus (HIV)positive patients receiving combination antiretroviral therapy (cART) [1, 2]. Interestingly, while inflammation/coagulation and gut damage were independently associated with mortality and non-AIDS morbidity, T-cell activation was not significantly related to these outcomes. CD38 is commonly regarded as a Tcell activation marker, and circulating CD38CD8 T cells have been strongly correlated with disease progression in untreated HIV infection [3, 4]. Upon suppressive cART, levels of CD38CD8 T cells remain abnormally elevated [5], and yet their prognostic significance is less clear [6, 7]. Whether activated T cells are associated with increased morbidity/mortality is not a trivial question, given the need for novel interventions to contain excessive inflammation/immune activation during cART and surrogate biomarkers of clinical outcome. The data reported by Tenorio et al and Hunt et al for relatively large cohorts of virologically suppressed subjects seem to conclude that CD38 expression on CD8 T cells does not associate with disease outcome. The apparent discrepancy with results from untreated patients led us to speculate regarding the existence of CD38CD8 subpopulations with a distinctive phenotype and function in cART-naive HIV-positive individuals, compared with HIV-positive cART recipients. We therefore investigated the immune phenotype and function of CD4/CD8 CD38 and CD4/CD8CD38 subsets in 31 HIV-positive patients followed at the Clinic of Infectious Diseases, University of Milan, San Paolo Hospital. Twelve were untreated (CD4 T-cell count, 633 cells/mm; interquartile range, [IQR] 425–687 cells/mm), 19 were receiving virologically suppressive cART (CD4 T-cell count, 534 cells/mm; IQR, 214– 752 cells/mm; HIV RNA load, <40 copies/mL; median time to first suppression, 4 years), and 10 were HIV-negative healthy donors (controls). As expected, untreated HIV-positive patients displayed a higher proportion of CD8CD38 cells than HIV-negative subjects (28% vs 8%; P = .0001). HIVpositive cART recipients showed decreased CD8CD38 levels, which, however, remained higher than those measured in controls (17% vs 8%; P = .004). As shown in Figure 1A, untreated patients had significantly lower proportions of naive CD38CD45RACD45R0 cells than HIV-negative patients (52% vs 77% of CD4CD38 T cells [P = .013]; 59% vs 79% of CD8CD38 T cells [P = .002]) and higher proportions of memory CD38CD45RACD45R0 cells (52% vs 30% of CD4CD38 T cells [P = .012]; 48% vs 30% of CD8CD38 T cells [P = .008]). Interestingly, naive CD38CD45RA CD45R0 T cells were enriched in HIVpositive cART recipients, compared with untreated patients (72% vs 52% of CD4 CD38 T cells [P = .016]; 74% vs 59% of CD8CD38 T cells [P = .002]), and proportions were similar in HIV-positive cART recipients and HIV-negative subjects (72% and 77% of CD4CD38 T cells, respectively [P = .781]; 74% and 79% of CD8 CD38 T cells, respectively [P =.205]). In

the journal of infectious diseases (online. university of chicago press)/the journal of infectious diseases

Immunophenotype and Function of CD38-Expressing CD4+ and CD8+ T Cells in HIV-Infected Patients Undergoing Suppressive Combination Antiretroviral Therapy