Human Immunodeficiency Virus (HIV) emerged as a devastating global health crisis decades ago, initially presenting as a rapidly progressing and often fatal illness. Significant scientific advancements have since transformed HIV into a manageable, chronic condition for many individuals, particularly with the widespread availability of antiretroviral therapy (ART). This medical progress allows people living with HIV to lead long and healthy lives by suppressing the virus. Despite these successes, the ongoing need for daily medication highlights the persistent pursuit of an HIV cure.
Defining a Functional Cure
The concept of an HIV cure encompasses two main aspirations: a sterilizing cure and a functional cure. A sterilizing cure aims for the complete eradication of all replication-competent HIV from the body, meaning the virus would be entirely absent and pose no further threat. While a sterilizing cure remains a long-term goal, it is currently extremely challenging due to the virus’s ability to hide in cellular reservoirs.
In contrast, a functional cure, also referred to as “medicine-free remission” or “long-term viral control off ART,” means the virus is suppressed to undetectable levels without the need for daily antiretroviral therapy. Here, the virus is not completely eliminated but remains under the immune system’s control, preventing illness or transmission. Researchers widely consider a functional cure a more achievable and scalable objective compared to a sterilizing cure. Controlling the virus without continuous medication would significantly improve lives.
Approaches to Achieving Remission
Achieving a functional cure involves targeting the mechanisms by which HIV persists and evades the immune system. Current scientific strategies focus on various experimental therapies to control or eliminate the virus without daily ART. These approaches aim to address the latent viral reservoirs, which are dormant HIV-infected cells that current ART cannot reach.
Latency Reversal Agents (LRAs)
One strategy uses Latency Reversal Agents (LRAs), sometimes referred to as a “kick and kill” approach. HIV can integrate its genetic material into the host cell’s DNA, becoming latent and invisible to the immune system and ART. LRAs are designed to “wake up” these dormant viruses, forcing them from hiding places. Once reactivated, these infected cells become visible targets for the immune system to clear, or for additional therapies to eliminate.
Immunotherapy
Immunotherapy is another approach, focusing on boosting the body’s own immune response against HIV. This includes broadly neutralizing antibodies (bNAbs). These special antibodies can recognize and neutralize a wide range of HIV strains, unlike typical antibodies targeting specific viral variations. By administering bNAbs, scientists aim to provide the immune system with powerful tools to directly attack and control the virus, potentially reducing the viral reservoir or preventing new infections.
Gene Therapy
Gene therapy and gene editing techniques modify immune cells to resist HIV infection. One method edits the CCR5 gene, which encodes a co-receptor that most HIV strains use to enter CD4+ T-cells. By disabling or removing this CCR5 receptor, gene therapy aims to create immune cells inherently resistant to HIV, effectively building a new, protective immune system. This modification can be performed on a patient’s own cells, then reintroduced.
Therapeutic Vaccines
Therapeutic vaccines are also being investigated to train the immune system to control the virus more effectively. Unlike preventive vaccines, which stop infection, therapeutic vaccines are given to people already living with HIV. These vaccines seek to induce a robust and sustained immune response that can keep the virus in check without ART. By enhancing the body’s ability to recognize and fight HIV-infected cells, therapeutic vaccines could lead to long-term remission.
Immune Checkpoint Inhibitors (ICIs)
Immune checkpoint inhibitors (ICIs), primarily known for their role in cancer treatment, are being explored for HIV. These drugs work by blocking certain proteins that act as “brakes” on immune cells, thereby reinvigorating the immune response. In HIV, ICIs may help exhausted T-cells regain their ability to fight the virus and potentially reverse HIV latency, making infected cells more vulnerable to elimination. While promising, safety concerns and potential side effects require careful consideration in their application for HIV.
Current Research Landscape
The journey toward an HIV functional cure has seen significant milestones, although widespread availability remains a future goal. Notable cases of individuals achieving long-term HIV remission, primarily through complex medical interventions for other conditions, provide valuable insights into potential cure strategies. These cases have demonstrated that an HIV cure, while challenging, is possible.
Timothy Ray Brown
Timothy Ray Brown, known as the “Berlin Patient,” was the first person considered cured of HIV. In 2007, he received two stem cell transplants to treat acute myeloid leukemia from a donor with a rare genetic mutation (CCR5-delta-32). This mutation provides natural resistance to HIV by preventing the virus from entering cells. Brown remained free of HIV without ART until his passing from leukemia in 2020, demonstrating the potential for a sterilizing cure under specific circumstances.
Adam Castillejo
Following Brown’s case, Adam Castillejo, the “London Patient,” achieved sustained HIV remission after a similar stem cell transplant in 2016 for Hodgkin’s lymphoma. Castillejo stopped ART and has shown no detectable active HIV for over two-and-a-half years, further supporting the potential of this approach. His case indicated that a less intensive chemotherapy regimen than Brown’s might be effective.
New York Patient
More recently, a “New York Patient,” a mixed-race woman, was reported in HIV remission following a stem cell transplant for leukemia in 2017. This case is significant as it involved umbilical cord blood stem cells, which may broaden the pool of potential donors, especially for diverse racial and ethnic backgrounds where CCR5-delta-32 donors are rarer. These cases, while rare and involving high-risk procedures for life-threatening cancers, offer proof-of-concept for HIV cure research.
Ongoing Research
Ongoing research explores translating these highly specific and risky procedures into more broadly applicable therapies. Scientists investigate strategies not requiring intensive treatments, focusing on approaches like gene therapy and immune-based interventions. The primary challenge remains the eradication of the latent viral reservoir, difficult to access and eliminate. Researchers also work on methods to accurately measure this reservoir and ensure any potential cure is durable and safe.
Impact on Global Health
The widespread availability of an HIV functional cure would impact individuals with HIV and global public health. For individuals, a functional cure would mean freedom from the daily regimen of antiretroviral therapy, which can be burdensome due to side effects, adherence, and lifelong psychological impact. This would significantly improve quality of life, allowing individuals to live without the constant reminder of their HIV status.
Reducing Stigma
A functional cure could also reduce the stigma associated with HIV, which persists despite advances in treatment and prevention. Eliminating the need for daily pills and rendering the virus undetectable and untransmittable without medication would foster greater social acceptance and reduce discrimination. This shift could lead to more open discussions about HIV and encourage testing and care.
Global Health Perspective
From a global health perspective, a widely accessible functional cure could alter the trajectory of the HIV epidemic. While current ART makes HIV manageable, over 40 million people living with HIV worldwide still present a substantial healthcare burden. A cure could reduce healthcare costs associated with lifelong ART, monitoring, and managing complications.
Simplifying Prevention
A functional cure could simplify prevention efforts by reducing the pool of individuals who transmit the virus. This would accelerate progress toward ending the HIV epidemic, especially in low- and middle-income countries where consistent ART access remains a challenge. While a functional cure is not yet widely available and ART remains the standard of care, ongoing research offers hope for a future where HIV is no longer a lifelong condition.