Immune non‐response despite effective antiretroviral therapy in people living with HIV : A review of potential mechanisms, biomarkers and therapeutic approaches

INTRODUCTION: A proportion of people living with HIV (PLWH) fail to restore their CD4 count or their CD4/CD8 ratio despite effective antiretroviral therapy (ART). PLWH with immune non-response (INR) are at a higher risk of both AIDS and non-AIDS events. The underlying mechanisms of INR remain unclear. OBJECTIVES: This review aims to explore the potential mechanisms of INR, focusing on the production, maturation and early destruction of CD4 cells. Additional factors such as age, proinflammatory environment or persistent viral infections like HIV or CMV may also contribute to INR. Biomarkers, such as microRNA, IL-6, soluble CD14 and soluble GP120, may help better characterize INR in PLWH. Despite various therapeutic attempts - including ART intensification and IL-2 or IL-7 administration - no strategy has yet succeeded in restoring effective CD4 T-cell recovery in INR. CONCLUSION: A lack of consensus on the definition and classification of INR limits research comparability and therapeutic progress. A standardized framework would facilitate mechanistic insights and guide the development of targeted treatments, including IL-7 therapy. In this review, we examine the putative mechanisms underlying INR in PLWH, prognostic markers and the therapeutic strategies that have been evaluated, albeit with limited success.