Immune-inflammatory biomarkers associated with depression in people with HIV: a systematic review

Depression is common in people with HIV (PWH) and may be partly related to persistent immune activation despite effective antiretroviral therapy. We systematically evaluated the consistency, magnitude, and temporal direction of associations between depression and inflammatory or immune-related biomarkers in PWH. PubMed/MEDLINE, Embase, Web of Science, Scopus, and CENTRAL were searched from inception to May 31, ​2026. Eligible studies included adults with HIV in whom depression was assessed using validated instruments or standardized diagnostic criteria. Circulating inflammatory and immune-related biomarkers were the primary outcomes; mechanistically relevant metabolic, neurobiological, and oxidative-stress measures were considered separately. Methodological quality was assessed using design-specific Joanna Briggs Institute checklists. Owing to substantial heterogeneity, findings were synthesized narratively; where feasible, effect estimates were harmonized to an r-equivalent metric for graphical assessment. Twenty-eight studies were included, most of which were observational and cross-sectional. Biomarker–depression associations were generally modest, heterogeneous, and frequently null. The most recurrent signals involved IL-6, C-reactive protein, TNF-related pathways, and markers of monocyte–macrophage activation, particularly sCD14, sCD163, and neopterin, although no biomarker showed a consistent association across studies. In several studies, inflammatory markers were more strongly associated with somatic or neurovegetative than with cognitive-affective symptoms. Evidence for tryptophan–kynurenine metabolism, monoaminergic signaling, neuroinflammation, mitochondrial dysfunction, and oxidative imbalance was more limited and exploratory. Longitudinal studies suggested possible bidirectional associations between depressive symptoms and immune activation. Current evidence is compatible with an immune-inflammatory contribution to depression in PWH but does not support a consistent or depression-specific biomarker signature. Predominantly cross-sectional designs, heterogeneity, and residual confounding limit causal inference and clinical applicability. Longitudinal studies with repeated biomarker assessment, standardized depression phenotyping, and comprehensive confounder control are needed. PROSPERO CRD420261360464.