Abstract

Chronic human immunodeficiency virus (HIV) infection was characterized by progressive immune dysfunction, in 
which CD4+ T cell depletion and exhaustion play pivotal roles. CD4+ T cell exhaustion, marked by impaired 
proliferative capacity and sustained expression of inhibitory receptors, contributes to poor immune reconstitution 
despite effective antiretroviral therapy. Biomarkers such as programmed cell death protein 1 (PD-1), T cell 
immunoglobulin and mucin-domain containing-3 (TIM-3), cytotoxic T lymphocyte antigen 4 (CTLA-4), and 
lymphocyte activation gene 3 (LAG-3) had been proposed as key indicators of T cell dysfunction, while soluble 
inflammatory mediators provide complementary prognostic information. The purpose of this review was to 
critically evaluate the prognostic implications of CD4+ T cell exhaustion biomarkers in chronic HIV infection, 
focusing on their utility for predicting disease progression, therapeutic outcomes, and comorbid risks. A narrative 
synthesis was conducted using PubMed, Scopus, and Web of Science databases for studies published between 2012 
and 2025, including clinical trials, mechanistic investigations, and translational studies of immune biomarkers in 
HIV. Evidence indicated that high expression of PD-1 and TIM-3 correlates with accelerated CD4+ decline, higher 
viral reservoirs, and increased risk of opportunistic infections. Combinatorial biomarker profiling enhanced 
prognostic accuracy beyond single markers. Importantly, exhaustion biomarkers also predicted responsiveness to 
immune-based therapies and vaccine strategies. Despite their promise, variability across cohorts and technical 
limitations hindered standardization. CD4+ T cell exhaustion biomarkers provided valuable insights into HIV 
pathogenesis and may guide prognostic assessment and therapeutic innovation. 
Keywords: HIV, CD4+ T cell, Immune exhaustion, Biomarkers, Prognosis.