Determinants of HIV post-intervention control after HTI-based therapeutic vaccination in early-treated individuals

Abstract

Despite significant advances in antiretroviral therapy (ART), a definitive cure for human immunodeficiency virus (HIV) remains elusive for the 39 million people living with HIV (PWH) worldwide who continue to experience stigma, lifelong medication burdens, and health disparities. The primary obstacle to curing HIV is the persistence of an HIV reservoir, which consists of a pool of cells in which HIV's genome is integrated into the host's DNA. Viral replication can rapidly restart upon ART discontinuation, and the host's antiviral immune response is unable to contain this viral resurgence. Significant efforts have been made over the last 20 years of HIV cure research, aimed at reducing or perturbing the viral reservoir and training the immune system to detect and eliminate HIV-1 infected T cells. Importantly, cure clinical trials face several challenges. In the absence of validated biomarkers able to predict post-intervention virological control after ART cessation, analytical treatment interruptions (ATI) and inclusion of placebo groups are the only reliable tools to assess the efficacy of a tested strategy. However, ATI harbor several logistical and ethical challenges. Community-driven advocacy has played a pivotal role in shaping the HIV cure research agenda, as well as in reinforcing the necessity of exploring innovative approaches when designing and implementing HIV remission trials. The continued engagement of PWH in clinical trials underscores the collective determination to move beyond ART dependency toward sustainable remission solutions. In this thesis, I aimed to evaluate the safety, immunogenicity, and efficacy of a novel therapeutic vaccine for HIV, based on the HIVACAT T-cell immunogen (HTI), alone or in combination with the TLR7 agonist Vesatolimod (VES), in PWH treated within the first six months after HIV acquisition in two independent, randomized, double-blinded, placebo-controlled clinical trials. After the introduction, I provide the description of the Early-cART cohort as a research platform from which potential candidates for the discussed HIV cure trials described in Articles 1 and 2 were identified. We also evaluate the impact of the implementation of the Early-cART cohort on the reduction in the time from HIV acquisition to ART initiation in individuals newly diagnosed of HIV in the acute and recent phase of infection and the immunovirological outcomes of early ART initiation. In Article 1 of the compendium, I present the results of the first clinical trial evaluating a combination of HTI-based vaccines in early-treated individuals: the AELIX-002 trial. AELIX-002 demonstrated that HTI vaccines were safe and immunogenic, inducing strong, polyfunctional, and broad CD4 and CD8 T-cell responses specific to HTI. Notably, AELIX-002 provided the first clinical signal of efficacy of a therapeutic HIV vaccine, with exploratory analyses suggesting that prolonged ART-free periods in vaccinated individuals lacking protective HLA alleles were associated with vaccine-induced HTI-specific T-cell responses. In Article 2 of the compendium, results from the AELIX-003 trial are presented. AELIX-003 study was built on finding from AELIX-002 and evaluated the combination of HTI vaccines with VES also in early treated individuals. Although the combination was safe and immunogenic, no clear additional benefit over HTI vaccination alone was observed in terms of viral control. However, VES may have contributed to maintaining robust HTI-specific responses through a less complex vaccination regimen. I then discuss the implications of results from both studies in the HIV cure field, and how can these results can provide clues for the developing future strategies. Finally, in the future perspectives section, I provide an integration of individual participant's data from AELIX-002 and AELIX-003 in a pooled analysis, leveraging the large and homogeneous cohort to validate immunological correlates of ATI outcomes and to explore additional biomarkers predictive of extended ART-free periods and improved viral control during ATI.

Date of Award	19 Sept 2025
Original language	English
Supervisor	Jose Molto Marhuenda (Director) & Beatriu Mothe Pujades (Director)