The Human Immunodeficiency Virus (HIV) remains a global health challenge, despite the success of modern Antiretroviral Therapy (ART). While daily ART effectively suppresses the virus to undetectable levels, allowing people to live long, healthy lives, it is a lifetime commitment and does not eradicate the infection. If ART is stopped, the virus almost always rebounds, necessitating a permanent solution beyond chronic management. Global research efforts are focused on developing strategies to achieve a true cure, seeking to eliminate the virus entirely or to control it long-term without the need for medication.
Defining the Goal Functional vs Sterilizing Cure
The pursuit of an HIV cure is divided into two objectives: a sterilizing cure and a functional cure. A sterilizing cure represents the complete elimination of all replication-competent HIV from the body. This is the traditional definition of a cure, where no trace of the virus capable of causing infection remains. Documented cases of cure achieved through high-risk medical procedures fall into this category, demonstrating it is biologically possible.
A functional cure, often called long-term remission, allows the patient to stop ART permanently. In this scenario, a small amount of the virus may still persist, but the patient’s immune system controls it effectively without medication. The viral load remains suppressed below detectable levels, preventing disease progression and transmission. This approach is analogous to remission seen in some cancer treatments.
Targeting Latency Strategies to Expose the Hidden Virus
The primary obstacle to both forms of cure is the viral reservoir, the pool of dormant HIV DNA integrated into the chromosomes of host cells. This integrated viral DNA, or provirus, is transcriptionally silent, meaning it does not produce new viral proteins or particles. The reservoir primarily consists of resting memory CD4+ T cells, which are long-lived immune cells.
ART targets actively replicating virus and cannot affect these silent, infected cells, allowing the provirus to evade medication and the immune system. The latent reservoir has an extremely long half-life, which is why stopping treatment leads to viral rebound. Therefore, any curative strategy must eliminate this hidden pool of infected cells.
The Shock and Kill Strategy
One studied strategy to address this reservoir is the “Shock and Kill” approach. The “shock” phase uses specialized compounds called Latency-Reversing Agents (LRAs) to force the dormant HIV provirus to become transcriptionally active. This process causes the infected cell to start producing viral proteins, essentially unmasking the infected cells.
The subsequent “kill” phase relies on the host’s immune system or targeted therapies to recognize and destroy the newly activated, virus-producing cells. Examples of LRAs include Histone Deacetylase (HDAC) inhibitors and Protein Kinase C (PKC) agonists. While LRAs successfully activate the virus in clinical trials, the challenge remains in efficiently clearing all reactivated cells to eliminate the entire reservoir.
Genetic and Immunological Modification Approaches
A separate class of cure strategies focuses on permanently modifying the patient’s cells or enhancing the immune response. Evidence that a sterilizing cure is possible comes from patients who received Hematopoietic Stem Cell Transplants (HSCT) for concurrent blood cancers. For these patients, including the “Berlin Patient” and “London Patient,” the cure was achieved by transplanting stem cells from donors who possessed a rare genetic mutation.
Stem Cell Transplants
This mutation, known as CCR5-delta32, prevents the virus from entering T-cells by removing the CCR5 receptor, a primary entry point for HIV. The high-risk procedure involves aggressive chemotherapy followed by the infusion of donor stem cells that rebuild the immune system with HIV-resistant cells. While successful for this small group, the procedure is too dangerous and resource-intensive to be a scalable cure for the general population. However, the case of the “Geneva Patient,” who achieved remission without the protective mutation, suggests the powerful “graft-versus-reservoir” immune reaction also plays a significant role.
Gene Editing
Gene editing technologies, particularly CRISPR/Cas9, offer a way to mimic the protective CCR5-delta32 mutation without a full stem cell transplant. Researchers are exploring using CRISPR to edit the CCR5 gene in a patient’s own T-cells or hematopoietic stem cells, making them resistant to HIV infection. A more direct application is attempting to “cut out” the integrated HIV provirus from the host cell’s DNA, removing the genetic blueprint of the virus. Challenges remain in ensuring the editing is precise across all infected cells and avoiding unintended changes to the host genome.
Immunotherapy
Immunotherapy approaches aim to bolster the body’s natural defenses to clear the virus and control the reservoir. One method involves Broadly Neutralizing Antibodies (bNAbs), potent antibodies capable of neutralizing a wide range of HIV strains. These antibodies can be infused to neutralize circulating virus and enhance the immune system’s ability to kill infected cells.
Another technique is the development of engineered T-cells, such as Chimeric Antigen Receptor (CAR) T-cells. These cells are genetically modified to specifically recognize and attack HIV-infected cells, providing a targeted “kill” mechanism for the reactivated reservoir. Combination therapies using bNAbs and immune-boosting agents have demonstrated the ability to maintain viral control for months after stopping ART, offering a path toward long-term ART-free remission.