Table 3.

Summary of Results of Included Studies Examining Immune Activation (k = 13).

Author	Follow-up duration	Depression variable(s)	Immune activation variable(s)	Covariates	Results
Randomized controlled trial
Gupta [51]	24 weeks	Intervention (internet cognitive-behavioral therapy) vs. usual care	12 week change in sCD14 24 week change in sCD14 12 week change in sCD163 24 week change in sCD163 12 week change in sVCAM-1 24 week change in sVCAM-1	None.	Observed a larger mean reduction in sCD14 in the intervention group than usual care at 12 (p = .014) but not 24 weeks (p = .108). Observed a larger mean reduction of sCD163 in the intervention group than usual care at 24 (p = .024) but not 12 weeks (p = .622). No group differences observed in sVCAM-1 at 12 or 24 weeks (ps NR).
Longitudinal
Lu [54]	Median = 4 visits (duration in time metric NR)	CES-D Measured at each semiannual visit. Multiple definitions examined: clinically relevant depression (>20), mild depression (12–20), and no depression (<12); CES-D ≥ 16; inclusion of antidepressant medication in prior 2 definitions (current use at time of measurement).	EIP characterized by immune activation markers sTNF-RII, sIL-2Ralpha, sCD27, B-cell activating factor, IP-10, sIL-6R, sCD14, and sGP130. Biomarkers measured at “selected study visits”.	Age, black race, college education, current smoking, obesity, hepatitis C infection, alcohol intake, and cocaine use.	A 1-SD higher EIP was associated with increased odds of clinical (OR = 1.09, 95% CI: 1.03–1.16, p NR) and mild (OR = 1.09, 95% CI: 1.03–1.16, p NR) depression. Similar results were observed for clinical depression with antidepressant inclusion (OR = 1.11, 95% CI: 1.05–1.18, p NR). No moderation was observed by ART use, HIV suppression status, or pre- vs. post- cART era. Similar results were also observed using a different CES-D cut-off without (OR = 1.08, 95% CI: 1.02–1.14, p NR) and with (OR = 1.09, 95% CI: 1.03–1.16, p NR) antidepressant inclusion. Similar results were also observed when the EIP was defined by highest vs. lowest tertiles for clinical depression with (OR = 1.21, 95% CI: 1.05–1.39, p NR) and without (OR = 1.21, 95% CI: 1.06–1.37, p NR) the inclusion of antidepressants.
McGuire [55]	Mean = 3.2 years	CES-D Measured at 6-, 12-, and 24 months.	CD8+/CD38+ Measured at baseline.	Sex, race, recent psychiatric care, recent illicit drug use, and recent alcohol use.	Higher levels of CD8+/CD38+ were associated with lower depressive symptoms at 12 months (β = −.954, 95% CI: −1.854 to .054, p = .038). Results were similar when examining outcomes at 6 and 24 months.
Veenhuis [56]	Median = 1 year	CES-D Measured at follow-up.	% CD14+CD16+ of subset of MNCs with TLR2+ Measured at baseline.	None.	No significant correlation between baseline % of CD14+CD16+ of MNCs subset and depressive symptoms at follow-up (rs = .23, p NR).
Cross-sectional
Evans [57]	N/A	Current MDD (structured clinical interview) HDRS-17 HDRS-11 (excludes somatic symptoms)	CD8+/CD38+/DR+	ART use and viral load.	MDD was not correlated with CD8+/CD38+/DR+ (r = .18, p = .22). Depressive symptoms, as measured by the HDRS-17 and HDRS-11 (excludes somatic symptoms), were positively correlated with CD8+/CD38+/DR+ (r = .30, p = .03; r = .28, p = .05, respectively).
Gold [58]	N/A	BDI-II POMS-Depression-Dejection	CSF neopterin	None.	Depressive symptoms, as assessed by either measure, were not correlated with CSF neopterin (ps NR).
Greeson [59]	N/A	BDI	CD3+/CD8+/CD38+ CD3+/CD8+/HLADR+	None.	Depressive symptoms were not correlated with CD3+/CD8+/CD38+ (r = .06) or CD3+/CD8+/HLADR+ (r = .05, ps>.05).
Hellmuth [60]	N/A	PHQ-9 ≥ 10 HADS-D ≥ 8	Plasma neopterin CSF neopterin	Viral load, CD4 count, and time on ART (or time since diagnosis).	Depression, as defined by PHQ-9 and HADS-D, was positively associated with plasma neopterin (p = .001 and .007, respectively), controlling for covariates. PHQ-9 was correlated with plasma neopterin (r = .29, p = .045). Depressed group defined by either measure had higher plasma (p = .011) but not CSF neopterin (p NR). Depressed group defined by HADS-D had higher CSF neopterin (p = .028).
Kemeny, 1994 [61]	N/A	POMS-Depression-Dejection	CD8+/CD38+	None.	Depression was correlated with CD8+/CD38+ among non-bereaved participants (r = .54, p < .01) but not among bereaved participants (r = −0.41, p NR).
Kemeny, 1995 [62]	N/A	POMS-Depression-Dejection	Neopterin CD8+/HLA-DR+ CD8-/HLA-DR+	In separate partial correlation analyses: alcohol, cigarettes, exercise, sleep hours, HIV-related symptoms, or sexual behavior.	Among bereaved participants, no significant correlations were observed between depression and neopterin, CD8+/HLA-DR+ or CD8-/HLA-DR+ (ps NR). Among nonbereaved participants, depression was correlated with CD8-/HLA-DR+ (r = .56, p < .05). This association remained significant when controlling for covariates in separate partial correlation analyses (r range = .54–.60, p < .05) and was unaffected by exclusion of participants with current drug use (r = .51, p < .10) or CNS impairment (r = .57, p < .05).
Schroecksnadel [63]	N/A	BDI ≥ 10	Plasma neopterin Urinary neopterin	None.	Depressed group had higher plasma and urinary neopterin than nondepressed group (p < .01). Both plasma (OR = 1.021, 95% CI: 1.004–1.024, p = .018) and urinary neopterin (OR = 1.002, 95% CI: 1.001–1.004, p = .003) were associated with depression. In the total sample, depression was positively correlated with neopterin (r = .295, p < .001). Among those not on an antidepressant, depression was positively correlated with neopterin (r = .331, p < .001) but not among those on an antidepressant.
Stewart [64]	N/A	PHQ-9 total depressive symptoms PHQ-9 somatic depressive symptoms PHQ-9 cognitive/affective depressive symptoms	sCD14	Age, sex, race/ethnicity, CVD, diabetes, hypertension, LDL-C, HDL-C, triglycerides, statin use, hepatitis C, renal function, hemoglobin, BMI, smoking, alcohol use, and cocaine abuse/dependence.	Non-significant positive trend for association between total depressive symptoms and sCD14 (exp(b) = 1.01, 95% CI: 1.00–1.03, p = .05–.10). No longer a trend with the addition of antidepressant medication, CD4 cell count, HIV RNA level, and ART use. A 1-SD increase in somatic depressive symptoms was associated with an increase in sCD14 (exp(b) = 1.02, 95% CI: 1.00–1.03, p < .05). Similar results were observed with the addition of antidepressant medication (p < .05), but this association became a nonsignificant trend with addition of CD4 cell count, HIV RNA level, and ART use (p = .5–.10). No significant association between cognitive/affective depressive symptoms and sCD14 (exp(b) = 1.01, 95% CI: 0.99–1.02, p NR). Similar results were observed with the addition of antidepressant medication, CD4 cell count, HIV RNA level, and ART use (ps NR).
Warriner [65]	N/A	BDI Cognitive/Affective (Cog-Aff) score	Neopterin	None.	Cog-aff symptoms were positively correlated with neopterin (r = .28, p < .05). Among those on an antidepressant, cog-aff symptoms were correlated with neopterin (r = .83, p < .001) but not among those not on an antidepressant (r = .03, p > .05). Cog-aff depression group (Cog-aff score >10) had higher neopterin than no depression group among those on an antidepressant (F = 45.7, df = 1,11, p < .001) but not among those not on an antidepressant (p > .05).
Veenhuis [56]	N/A	CES-D	% CD14+CD16+ of total MNCs %CD14+CD16+ of subset of MNCs with TLR2+	None.	No significant correlations between % of CD14+CD16+ defined as proportion of total MNCs (r = .01) or as proportion of subset of MNCs (r = .02, p NR) and depressive symptoms.

ART antiretroviral therapy; BDI Beck’s Depression Inventory; BMI body mass index; cART combined antiretroviral therapy; CEDS-D Center for Epidemiological Studies Depression Scale; CI confidence interval; CNS central nervous system; CSF cerebrospinal fluid; CVD cardiovascular disease; EIP exploratory factor analysis-identified inflammatory process; exp(b) = exponentiated beta regression coefficient; HADS-D Hospital Anxiety and Depression Scale; HDL-C high-density lipoprotein cholesterol; HDRS Hamilton Depression Rating Scale; HIV human immunodeficiency virus; IP-10 interferon gamma-induced protein 10; LDL-C low-density lipoprotein cholesterol; MDD major depressive disorder; MNC mononuclear cells: NR not reported; OR odds ratio; PHW-9 Patient Health Questionnaire-9; POMS Profile of Mood States; sCD14 soluble CD14; sCD27 soluble CD27; sCD163 soluble CD163; SD standard deviation; sGP130 soluble GP130; sIL-2Ralpha soluble interleukin-2 receptor alpha; sIL-6R soluble interleukin-6 receptor; sTNF-RII soluble tumor necrosis factor receptor II; sVCAM-1 soluble vascular cell adhesion molecule-1; TLR2 toll-like receptor 2.