The advent of antiretroviral therapy (ART) has fundamentally transformed the clinical course of HIV infection, transforming it from a historically fatal disease into a manageable chronic condition [1]. Contemporary evidence indicates that the majority of people living with HIV (PLWH) experience a marked reduction in plasma HIV RNA levels alongside substantial CD4+ T cell reconstitution following ART initiation. However, a clinically significant subset (15–30 %) of treatment-adherent individuals exhibits impaired immune reconstitution despite sustained viral suppression, maintaining persistently low CD4+ T cell counts over prolonged periods [[2], [3], [4]]. This subgroup, referred to as poor immunological responders (PIR), contrasts with good immunological responders (GIR), who achieve adequate CD4+ T cell restoration during suppressive ART [5]. Of particular concern, PIR with persistently diminished circulating CD4+ T cell levels are at increased risk for opportunistic infections, cardiovascular disease, neurocognitive impairment, metabolic disorders, and malignancies [[6], [7], [8], [9]]. Importantly, the pathophysiological mechanisms underlying suboptimal immune recovery in PIR remain poorly understood, representing a critical gap in current HIV research and therapeutics.

Addressing the mechanisms and determinants of PIR represents an urgent priority in HIV clinical research, with potential to mitigate immunologic non-response rates and improve therapeutic outcomes. While current evidence has identified pre-treatment CD4+ T cell count (baseline <200 cells/μL) and advanced age (>50 years) as established risk factors for suboptimal immune reconstitution, substantial heterogeneity remains in clinical trajectories [[10], [11], [12], [13]]. Notably, a significant subset of patients initiating ART with these risk factors ultimately achieve adequate CD4+ T cell recovery, suggesting that additional determinants modulate this process [14]. Emerging evidence highlights the pathological interplay between gut-derived microbial translocation and systemic inflammation in the pathogenesis of PIR. Multiple studies have documented elevated biomarkers of intestinal barrier dysfunction—including lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), and soluble cluster of differentiation 14 (sCD14)—in PLWH with impaired CD4+ T cell recovery [[15], [16], [17]]. These microbial byproducts translocate across compromised intestinal epithelia into systemic circulation, perpetuating a pro-inflammatory milieu through Toll-like receptor (TLR) signaling and subsequent immune hyperactivation [18]. Our previous work further demonstrated increased frequencies of activated CD4+ T cell subsets (CD4 + HLA-DR+) in PIR compared to GIR cohorts, suggesting that chronic antigenic stimulation exacerbates immune exhaustion [19]. Collectively, these findings implicate dysregulated inflammatory signaling—particularly imbalances within the cytokine network—as critical modulators of CD4+ T cell homeostasis.

Nevertheless, a comprehensive characterization of cytokine profiles linked to divergent immune recovery trajectories remains elusive. To bridge this knowledge gap, we performed high-dimensional proteomic profiling of 92 inflammatory cytokines in PLWH stratified by CD4+ T cell recovery status, aiming to (1) define cytokine signatures reflective of immune reconstitution capacity and (2) elucidate associations between inflammatory biomarkers and key clinical outcomes.