Human Immunodeficiency Virus (HIV) infection continues to pose a significant global health challenge, leading to acquired immunodeficiency syndrome (AIDS) if left untreated. While antiretroviral therapy (ART) has transformed HIV into a manageable chronic condition, it requires lifelong adherence and does not eliminate the virus entirely from the body. Gene therapy offers a new approach in the pursuit of an HIV cure or long-term remission. This method involves using genetic material to prevent or treat the disease by modifying a patient’s cells to resist infection or enhance their immune system’s ability to combat the virus.
The Core Concept: Modifying Cells to Fight HIV
Gene therapy for HIV involves altering a person’s genetic material to achieve two goals: rendering cells resistant to HIV infection or empowering immune cells to better target and eliminate HIV-infected cells. HIV primarily targets CD4+ T cells, a type of immune cell. By modifying these cells, or the stem cells that produce them, scientists aim to create a population of cells that can no longer be infected by the virus or can actively fight it.
One approach focuses on altering host cell genes, specifically those HIV uses to enter and replicate within cells. Another strategy involves introducing new genetic instructions into immune cells, turning them into specialized fighters against HIV. This modification can lead to the production of anti-HIV proteins or enhance the immune system’s natural ability to recognize and destroy infected cells. This aims to establish a durable population of resistant or virus-fighting cells within the body, potentially leading to long-term control of the infection.
Key Strategies in HIV Gene Therapy
Several specific gene therapy approaches are under investigation for HIV, each with a distinct mechanism of action. One strategy involves gene editing technologies like CRISPR-Cas9, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs). These tools allow for precise modifications to the host cell’s DNA, such as disrupting the CCR5 gene, a co-receptor HIV uses to enter cells. Modifying CCR5 can make CD4+ T cells resistant to many strains of HIV.
Another approach involves engineering immune cells, particularly T-cells, to express chimeric antigen receptors (CARs), creating CAR T-cells. These CAR T-cells are designed to recognize and target HIV-infected cells, leading to their destruction. This method has shown promise in cancer treatment and is now being adapted for HIV, with researchers exploring ways to make CAR T-cells durable and effective against the virus in various parts of the body.
Viral vectors are used to deliver these therapeutic genes into human cells. Lentiviruses and adeno-associated viruses (AAVs) are common choices because they can efficiently carry genetic material into target cells. These modified viruses are rendered harmless but retain their ability to deliver the desired genetic instructions, enabling the cells to acquire new anti-HIV properties, such as resistance to infection or the ability to produce broadly neutralizing antibodies.
Current Research and Clinical Trials
The field of HIV gene therapy is advancing, with research initiatives and clinical trials underway. Approaches that aim to disrupt the CCR5 gene have shown safety and persistence of gene-modified cells in human trials. For instance, a Phase 1 clinical trial in 2014 demonstrated that introducing ZFN-modified autologous CD4+ T cells with a mutated CCR5 was a safe approach, and some patients showed a decrease in viral loads after discontinuing antiretroviral therapy.
Ongoing clinical trials are exploring various gene editing technologies, including CRISPR-Cas9, for their ability to excise or inactivate the HIV provirus from infected cells. One such trial, EBT-101-001, is a Phase 1/2 study that uses an adeno-associated virus 9 (AAV9) to deliver a CRISPR-Cas9 system designed to attack the latent HIV proviral genome. Early results from this trial, presented in 2024, indicate the therapy was safe and well-tolerated, with one participant showing a delayed viral rebound and a significant drop in the HIV reservoir after stopping ART.
American Gene Technologies is also conducting research with their AGT103-T product, an autologous cell therapy that delivers gene-modified, HIV-specific CD4 T cells. This therapy has completed a Phase 1 trial and two antiretroviral withdrawal studies, showing safety and efficacy signals, and is now preparing for Phase 2. These ongoing studies represent steps towards a functional cure, aiming to reduce or eliminate the need for lifelong antiretroviral medication.
Implications and Considerations
The potential impact of HIV gene therapy is significant, offering the possibility of a functional cure or long-term remission, which could free individuals from the daily burden and side effects of lifelong antiretroviral therapy. A functional cure would mean the virus remains at undetectable levels in the body without the need for medication, while a sterilizing cure would completely eliminate the virus. Such advancements could also reduce the risk of HIV transmission and improve the quality of life for people living with HIV.
However, the development of gene therapy for HIV also comes with important considerations, particularly regarding safety and potential side effects. Researchers are monitoring for off-target gene editing, where the genetic tools might make unintended changes to the DNA, which could increase the risk of developing cancer later in life. Ethical considerations are also important, including ensuring scientific rationale, ensuring safety for participants, and transparently communicating both known and unknown risks. The goal is to proceed with the highest ethical standards, protecting individuals who volunteer for these early-phase trials.