Therapeutic HIV-1 Vaccines: A Cautious Perspective

More than 40 years after its discovery, HIV-1/AIDS remains a major global health threat, with nearly 41 million people living with HIV worldwide at the end of 2025. Antiretroviral therapy (ART) remains the only effective treatment; however, access to ART is still limited in many low- and middle-income countries due to inadequate infrastructure, high costs, and recent cuts in international funding. Despite advances in vaccine development, an effective prophylactic HIV-1 vaccine remains elusive, with no new efficacy trials currently planned. Consequently, the focus has shifted toward therapeutic HIV-1 vaccines as an adjunct to ART. Such vaccines may provide temporary immunological control of viral replication during ART interruption or failure and may reduce treatment costs by limiting the number of ART components. This review summarizes recent advances in therapeutic HIV-1 vaccines, including approaches that mimic T-cell responses of elite controllers, elicit broadly neutralizing antibodies, or redirect immunity toward viral epitopes essential for viral fitness, including drug-resistance mutations. To assess whether therapeutic vaccination may become a viable option for PLWH, we also review experience from routine vaccination in this population. This analysis provides a framework for designing therapeutic vaccination strategies, including dosage, regimens (priming/boosting), and durability of immune responses, thereby helping to determine revaccination needs. Although therapeutic HIV-1 vaccines alone are unlikely to achieve a sterilizing cure or sustained ART-free remission, accumulating evidence indicates that they can substantially enhance HIV-specific immunity, delay viral rebound following ART interruption, and complement various HIV-1 treatment strategies, making them an important component of combination approaches aimed at achieving a functional HIV-1 cure.