Learning from nature: HIV elite controllers as blueprints for a functional cure

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition but remains non-curative and requires lifelong adherence. Rare cases of long-term remission following stem cell transplantation (SCT) have demonstrated the possibility of viral eradication, yet this approach is not scalable or safe for global implementation. A unique subset of people living with HIV, known as elite controllers (ECs), can naturally suppress replication-competent HIV without ART, often for decades, while maintaining stable CD4 + T cell counts and showing no signs of disease progression. Their ability to sustain treatment-free viral suppression provides compelling evidence that durable remission is biologically achievable, offering a model for cure research. This review synthesizes current evidence on the biology of ECs, encompassing viral, intrinsic antiviral, genetic, and immune mechanisms that underlie natural control. It also examines demographic and clinical characteristics, landmark case reports, and the broader public health implications of elite control. Finally, insights from EC biology are discussed in relation to translational strategies such as gene editing, immune modulation, therapeutic vaccination, and reservoir-targeting approaches designed to mimic or reinforce natural control mechanisms. Understanding the determinants of viral suppression in ECs provides a biological blueprint for the development of a functional cure. As the field advances toward scalable, safe, and durable remission strategies, lessons from ECs remain central to achieving long-term viral control and ultimately ending the HIV epidemic.