HIV Cure Research: Progress and Barriers in Clinical Translation

Huxleigh Chilton^*
*Correspondence: Huxleigh Chilton, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA, Email:

Introduction

Since its identification in the early 1980s, the Human Immunodeficiency Virus (HIV) has claimed millions of lives worldwide. The development of combination antiretroviral therapy (cART) in the mid-1990s transformed HIV from a fatal disease into a manageable chronic condition. However, despite substantial advancements in treatment, a definitive cure remains elusive. Long-term ART is associated with side effects, stigma, lifelong financial burden and the risk of drug resistance. More importantly, ART does not eradicate the virus from the body but suppresses viral replication. The persistence of HIV in latent reservoirs long-lived, infected cells where the virus remains dormant is the major obstacle to achieving a cure. In recent years, HIV cure research has made significant strides, marked by high-profile cases of functional cures, novel therapeutic strategies and growing understanding of viral latency. However, the path from laboratory innovation to clinical translation remains fraught with complex scientific, ethical and logistical barriers. This article explores the current progress in HIV cure research and discusses the major challenges impeding its clinical implementation [1].

Description

HIV cure strategies fall into two main categories: sterilizing cure and functional cure. A sterilizing cure refers to complete elimination of all replication-competent virus from the body, while a functional cure implies long-term control of the virus without ongoing ART, even if small amounts of latent virus persist. The most notable examples of sterilizing cures are the â??Berlin Patientâ? and the â??London Patient,â? both of whom received bone marrow transplants from donors with a rare CCR5Î?32 mutation a genetic variant that prevents HIV from entering cells. These cases offered proof-of-concept that HIV can be cured under exceptional circumstances. However, such procedures are high-risk, expensive and not scalable for the global HIV population. As a result, attention has shifted to more broadly applicable approaches such as Latency-Reversing Agents (LRAs), gene editing, immune-based therapies and therapeutic vaccines [2].

One of the most actively researched strategies is the â??shock and killâ? approach, which uses LRAs to activate latent HIV in resting CD4+ T cells, making the virus visible to the immune system or susceptible to therapeutic intervention. Various agents including histone deacetylase inhibitors, protein kinase C agonists and toll-like receptor agonists have shown promise in reversing latency in vitro and in early-phase trials. However, clinical results have been mixed, with limited reductions in the size of the latent reservoir and concerns about toxicity. Another approach is â??block and lock,â? which aims to keep the virus in a deep latent state, preventing reactivation even in the absence of ART. While still in early stages, this strategy may offer a path to a functional cure with fewer side effects. Gene editing technologies such as CRISPR/Cas9 and zinc finger nucleases have emerged as powerful tools for targeting and eliminating proviral DNA from infected cells or modifying host cells to resist infection. Several experimental studies have demonstrated the ability of CRISPR systems to excise integrated HIV genomes in animal models. Researchers are also exploring gene therapy to knock out co-receptors like CCR5 or CXCR4 in hematopoietic stem cells to create HIV-resistant immune systems. However, off-target effects, delivery efficiency and long-term safety remain significant concerns for translating gene editing into human clinical practice. Another promising avenue is immune modulation through broadly Neutralizing Antibodies (bNAbs), checkpoint inhibitors and therapeutic vaccines. bNAbs have shown the ability to suppress viral replication and reduce reservoir size in animal models and early-phase human trials. Immune checkpoint inhibitors, used successfully in cancer therapy, may help reinvigorate exhausted HIV-specific T cells. Therapeutic vaccines aim to enhance the immune systemâ??s ability to recognize and eliminate infected cells, either alone or in combination with other interventions. Several vaccine candidates are in clinical development, using vector-based, DNA, mRNA, or protein platforms [2].

Despite these promising advances, translating HIV cure research into viable clinical therapies remains challenging. One of the greatest scientific barriers is the heterogeneity and persistence of latent reservoirs, which are established very early after infection and are distributed across various tissues, including lymph nodes, the central nervous system and the gastrointestinal tract. Current diagnostic tools are inadequate for accurately quantifying these reservoirs or predicting viral rebound after treatment interruption. Additionally, the risk of immune activation or off-target effects from latency-reversing agents, gene editing, or immune modulation requires careful consideration, especially in immunocompromised patients.

Conclusion

The quest for an HIV cure represents one of the most ambitious and necessary endeavors in modern medicine. While remarkable progress has been made in understanding HIV latency, viral reservoirs and host-virus interactions, significant challenges remain on the road to clinical translation. Advances in latency reversal, gene editing, immunotherapy and vaccine science have provided multiple potential pathways toward both sterilizing and functional cures. However, technical limitations, safety concerns, ethical dilemmas and socioeconomic barriers continue to hinder widespread clinical application. Moving forward, a successful cure strategy will likely involve a multimodal approach that combines virologic, immunologic and genetic interventions, tailored to the individual patient. To achieve this goal, continued investment in translational research, cross-disciplinary collaboration and global equity in access to innovation will be paramount. Ultimately, curing HIV will not only save lives but also symbolize a triumph of scientific perseverance and humanitarian commitment.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Sanchorawala, Vaishali. “Light-chain (AL) amyloidosis: Diagnosis and treatment.” Clin J Ame Soci Nephrol 1 (2006): 1331-1341.

Google Scholar                        Cross Ref                Indexed at

2. Baumgarth, Nicole. “How specific is too specific? Bâ?cell responses to viral infections reveal the importance of breadth over depth.” Immunol Rev 255 (2013): 82-94.

Google Scholar                        Cross Ref                Indexed at