Clinical Translation of Engineered Cell and Gene Therapies for HIV Cure: A Systematic Review and Target-Product-Profile Gap Analysis of Human Interventional Studies

Abstract

This systematic review evaluates the clinical translation of engineered cell and gene therapies developed for HIV cure, sustained remission, or durable antiretroviral therapy (ART)-free control. The review focuses on human interventional studies evaluating genetically engineered therapeutic products, including gene-edited CD4+ T cells, engineered T-cell and natural killer-cell therapies, chimeric antigen receptor (CAR)-based approaches, gene-modified hematopoietic stem and progenitor cells, and in vivo gene-editing or gene-delivery strategies. The review aims to characterize the clinical development landscape; evaluate safety, feasibility, cellular persistence and engraftment, target engagement, effects on the HIV reservoir, analytical treatment interruption outcomes, viral rebound, and ART-free virological control; and identify barriers that have limited translation from biological activity to clinically meaningful HIV remission or cure. Multiple reports arising from the same clinical trial will be linked at the trial-family level to avoid double counting of participants and outcomes. In addition to the systematic evidence synthesis, a structured target-product-profile gap analysis will compare clinical-stage strategies across translational domains including efficacy, safety, durability, breadth and resistance, delivery and conditioning requirements, manufacturing complexity, scalability, and implementation feasibility. The objective is to identify which characteristics of current platforms remain furthest from those required for a clinically deployable HIV cure strategy. Bibliographic databases, clinical-trial registries, and relevant conference proceedings are included. Full-text publications, eligible conference reports, and trial-registry records are considered according to predefined eligibility criteria. Registry-only and ongoing studies without clinical outcome data will be used to characterize the development landscape but will not contribute to quantitative efficacy estimates. This OSF registration is retrospective. Study identification, screening, and data extraction had commenced before registration. The registration is intended to transparently document the eligibility criteria, evidence-synthesis methods, trial-family framework, and target-product-profile domains used for the final analyses. Any subsequent deviations from these methods will be explicitly identified and justified in the final report.