Evidence for Persistent Monocyte and Immune Dysregulation After Prolonged Viral Suppression Despite Normalization of Monocyte Subsets, sCD14 and sCD163 in HIV-Infected Individuals

Anjana Yadav, Andrew V. Kossenkov, Vincent R. Knecht, Louise C. Showe, Sarah J. Ratcliffe, Luis J. Montaner, Pablo Tebas, Ronald Collman

Abstract


Background: People living with HIV on antiretroviral therapy (HIV/ART) experience excess non-AIDS comorbidities, and also remain at increased risk for certain infections and viral malignancies. Monocytes/macrophages are central to many of these comorbidities, and elevated plasma cytokines and immune activation during untreated infection are often incompletely reversed by ART and are also associated with comorbidities.

Methods: We investigated monocyte surface markers, gene expression, and plasma cytokines in 11 HIV-infected older individuals (median 53 years) who started therapy with low CD4 counts (median 129 cells/μl), with elevated hsCRP (≥ 2mg/L) despite long-term ART (median 7.4 years), along with matched controls.

Results: Frequency of monocyte subsets (based on CD14/CD16/CD163), were not different from controls, but surface expression of CD163 was increased (P = 0.021) while PD1 was decreased (P = 0.013) along with a trend for higher tissue factor (P = 0.096). As a group, HIV/ART participants had elevated plasma CCL2 (MCP-1; P = 0.0001), CXCL9 (MIG; P = 0.04), and sIL2R (P = 0.015), which were correlated, while sCD14 was not elevated. Principal component analysis of soluble markers revealed that 6/11 HIV/ART participants clustered with controls, while 5 formed a distinct group, driven by IL-10, CCL11, CXCL10, CCL2, CXCL9, and sIL2R. These individuals were significantly older than those clustering with controls. Transcriptomic analysis revealed multiple genes linked to immune functions including inflammation, immune cell development, and cell-cell signaling that were downregulated in HIV/ART monocytes and distinct from patterns in untreated subjects.

Conclusions: Long-term ART-treated individuals normalize monocyte subsets but exhibit immune dysregulation involving both aberrant inflammation and monocyte dysfunction, as well as inter-individual heterogeneity, suggesting complex mechanisms linking monocytes and HIV/ART comorbidities.


Keywords


HIV/AIDS; Antiretroviral therapy; Monocyte; Gene expression; Cytokine; Inflammation

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References


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Footnotes

Submitted September 23, 2019 | Accepted November 21, 2019 | Published December 17, 2019

Supplementary Materials

Supplementary Figure 1. Gating of monocyte subsets. Freshly isolated PBMCs from HIV+ and HIV- individuals were stained for monocyte surface markers and analyzed by flow cytometry. Representative dot plot showing monocyte subsets based on CD16 expression after gating on total CD14+ monocytes.

Supplementary Figure 2. Correlation analysis between soluble markers combining HIV/ART and HIV-negative participants. A Spearman correlation test was used to assess the significance of correlations between the measured parameters combining HIV/ART and HIV-negative participants. (A) Correlations between CXCL9, CCL2, CCL11, and IL-2R (sIL-2R). (B) Correlations between sCD14, CCL2, sCD163, and hsCRP. The correlation coefficient and significance values for each comparison are shown over each graph.

Supplementary Figure 3. Proportion of monocyte subsets expressing surface markers. (A) Percentage of classical (CD14++CD16-), (B) intermediate (CD14++CD16+), and (C) non-classical (CD14+CD16++) monocyte subsets from virally suppressed HIV/ART participants and matched HIV-negative controls expressing the indicated markers. Results are expressed as mean ± SE. P value is calculated using unpaired Mann Whitney U-test.

Supplementary Figure 4. Mean fluorescence intensity of surface markers on monocyte subsets. MFI of indicated markers on (A) classical (CD14++CD16-), (B) intermediate (CD14++CD16+), and (C) non-classical (CD14+CD16++) monocyte subsets from virally suppressed HIV/ART participants and matched HIV-negative controls. Results are expressed as mean ± SE. P value is calculated using unpaired Mann Whitney U-test.


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