The Journal of Infectious Diseases® 2015;212:839–41 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.
[email protected]. DOI: 10.1093/infdis/jiv166
Response to Bandera et al TO THE EDITOR—We thank Bandera et al for their interesting exploration of the relationship between innate immune activation phenotypes and the failure of immunologic reconstitution after initiation of antiretroviral therapy (ART), in response to our published findings [1]. They demonstrate an intriguing association between immunologic nonresponse (INR, CD4 < 350 cells/µL) and increased frequency of cellular markers of innate immune activation, particularly higher levels of intermediate (CD14++CD16+) monocytes, lower expression of CD163 on total and classical (CD14++CD16−) monocytes, and a higher proportion of intermediate monocytes expressing CD11b, all of which support a shift of monocyte phenotype away from classical monocytes and toward intermediate and nonclassical monocyte subtypes. Although their comparisons are unadjusted and the observed differences are small, their investigation is one of the first to examine the role of innate immune activation, and monocytes in particular, in INR. The question of causal direction remains, particularly whether proinflammatory cytokines drive both the failure of CD4 restoration and the observed skewing of the monocyte developmental Table 1.
progression away from the classical monocyte subset and toward dysfunctional, activated subsets, or whether innate immune activation, through activated monocyte subsets, increases inflammatory cytokines and activating CD4+ T cells causing INR. Motivated by the data from Bandera et al, we explored the associations between CD4 count and soluble markers of inflammation at baseline within the Study to Understand the Natural History of HIV/ AIDS in the Era of Effective Therapy (SUN Study). In our data set, participants with CD4 < 350 versus >500 cells/µL had a statistically significant higher frequency of CD14++CD16+ monocytes and higher levels of sCD163, sCD14, and interleukin (IL)–6 (Table 1). When evaluating CD4 count as a continuous variable in unadjusted models, findings were consistent in that CD4 count was inversely correlated with circulating levels of sCD163 (correlation [r] = − 0.162; P < .001), sCD14 (r = − 0.131; P < .001), and IL-6 (r = − 0.237; P < .001). These observed associations support the hypothesis put forth by Bandera et al that innate immune activation may be associated with poor CD4+ T-cell restoration; however, the associations with CD4 count that we found in the SUN Study were generally modest. Importantly, our published findings on associations between monocyte activation and clinical risk biomarkers of inflammation were adjusted for CD4 count, in addition to other important confounders. Ultimately, these data warrant further study to determine whether incomplete
Monocyte and Biomarker Distribution by CD4 Count CD4 < 350 cells/µL (N = 195) Median (IQR)
CD4 > 500 cells/µL (N = 289) Median (IQR)
P Value
CD14dimCD16+ CD14++CD16+
6.0 (3.6, 10.5) 6.0 (3.5, 8.5)
6.0 (3.6, 10.1) 4.9 (3.1, 7.1)
.81
