Human immunodeficiency virus (HIV) remains a global health challenge. While antiretroviral therapy (ART) has transformed HIV into a manageable chronic condition, it does not eliminate the virus from the body. ART requires lifelong adherence, and stopping treatment leads to viral rebound. The pursuit of an HIV cure remains an active research area.
Defining “Cure” in HIV Research
The term “cure” in HIV research carries specific meanings, distinguishing between two main goals: a sterilizing cure and a functional cure. A sterilizing cure involves the complete eradication of all replication-competent HIV, including the latent viral reservoir, from the body, eliminating any possibility of viral rebound.
In contrast, a functional cure aims for long-term remission where the virus is undetectable without antiretroviral therapy, but may still be present in very low, non-replicating amounts. In this scenario, the individual’s immune system or other interventions would control the virus sufficiently to prevent its replication or transmission. Achieving a sterilizing cure presents considerable challenges, primarily due to the integrated and latent nature of the viral reservoir, which can hide from both ART and the immune system.
Pioneering Cases of HIV Remission
Cases of long-term HIV remission have demonstrated that a cure is possible, offering insights for ongoing research. The landmark case of the “Berlin Patient,” Timothy Ray Brown, was the first HIV cure. He underwent a bone marrow transplant in 2007 to treat leukemia, receiving stem cells from a donor with a genetic mutation, CCR5-delta32. This mutation renders immune cells resistant to HIV strains, effectively creating a new, HIV-resistant immune system.
Following this case, subsequent successes, such as the “London Patient” (Adam Castillejo), have confirmed this approach. These individuals also received stem cell transplants from donors with the CCR5-delta32 mutation for co-occurring cancers, leading to sustained HIV remission without ART. These cases underscore the potential of modifying the immune system to resist HIV.
The “Mississippi Baby” case, while initially promising, highlighted the complexities of early intervention. This infant received ART shortly after birth and achieved remission for a period after treatment cessation. However, the virus eventually rebounded, illustrating that early treatment alone may not be sufficient to achieve a lasting cure if a reservoir is established or reactivates.
Targeting the Viral Reservoir
A key challenge in curing HIV lies in the latent viral reservoir. This reservoir consists of HIV DNA integrated into the host cell’s genome, primarily within resting memory CD4+ T cells, where it lies dormant and is inaccessible to ART or the immune system. These latently infected cells do not actively produce new virus particles, making them invisible to current treatments. If ART is stopped, these viruses can reactivate and lead to viral rebound.
One major research strategy to address the reservoir is “Shock and Kill.” This approach involves using latency-reversing agents (LRAs) to activate dormant virus within the latent reservoir, forcing infected cells to produce viral proteins. Once activated, these cells become visible targets for the immune system or antiviral drugs, allowing for their elimination. While LRAs can reactivate the virus, they alone have not been sufficient to significantly reduce the size of the reservoir, indicating the need for a robust “kill” component to clear the reactivated cells.
Another strategy is “Block and Lock,” which aims to permanently silence the latent virus. This approach seeks to induce deep latency, preventing the virus from reactivating and replicating. This would effectively lock the virus in its dormant state, rendering it harmless without requiring its physical removal from the body. Researchers are exploring various compounds that can maintain this silenced state.
Gene therapy and gene editing approaches represent a different avenue for targeting the reservoir. Techniques such as CRISPR-Cas9 and zinc finger nucleases are being investigated to directly modify host cells. This modification can involve excising the integrated provirus from infected cells. Alternatively, gene editing can be used to engineer host cells to resist HIV infection by altering genes like CCR5, thereby making the cells impervious to viral entry and replication.
Enhancing the Immune Response
Research also focuses on strengthening the body’s immune system to control or clear HIV. Therapeutic vaccines are being developed to boost the immune response in individuals already living with HIV. These differ from preventative vaccines, aiming to train the immune system to recognize and control the virus.
Broadly neutralizing antibodies (bNAbs) are being explored for immune enhancement. These powerful antibodies can neutralize a wide range of HIV strains, making them attractive candidates for viral control or preventing viral rebound if ART is stopped. Clinical trials are investigating the use of bNAbs to suppress viral replication and potentially lead to remission.
Chimeric Antigen Receptor (CAR) T-cell therapy, adapted from cancer treatments, is also being explored for HIV. This involves engineering a patient’s own T-cells to express CARs, which are synthetic receptors designed to specifically recognize and bind to proteins on HIV-infected cells. Once bound, these engineered CAR T-cells can then destroy the infected cells, enhancing the body’s ability to clear the virus. This approach aims to empower the immune system to identify and eliminate HIV-infected cells that might otherwise remain hidden.