The continued search for a cure to HIV

Not very long ago, contracting HIV was an effective death sentence; today, there are treatments that allow the condition to be managed but not eradicated. Ben Hargreaves outlines how research is revealing new aspects of the virus and how the scientific community is making progress in the search for a cure.

People living with AIDS prior to the emergence of treatments had an average lifespan of just eight to ten years once infected with HIV. Fortunately, since the emergence of the first treatment in 1987 and the development of effective countermeasures, the condition is no longer a terminal one. With the option to medicate with pre-exposure prophylaxis (PrEP), the chance of transmitting HIV from sex or drug use through injection has also been greatly reduced.

The reason there has been, as yet, no effective cure for the condition is due to the complexity of the virus and the way in which it is activated within the body. At a basic level, the virus’s protein ‘coat’ and the enzymes it uses to gain control of the host cell’s DNA mutate frequently, making it difficult to target with therapeutics. Once a person contracts HIV, the virus’s method of duplication also poses challenges, as it commandeers the body’s own immune system and is able to build a ‘HIV reservoir’ of dormant immune cells that can become active again if treatment is stopped. Despite the obstacles, however, there are persistent efforts underway to better understand the virus with the end goal of developing a functional cure or effective vaccine against the virus.

Understanding the virus

AIDS was first identified in the US in 1981, but four decades later scientists are still learning exactly how the virus that causes the condition is structured and how the body reacts, or fails to react, once infected. The Salk Institute recently made a breakthrough on the former subject by determining the molecular structure of HIV Pol, a protein that plays a role in the virus’ replication. The team found that HIV Pol is formed by two proteins bound together, which was unexpected as other similar viral proteins are single-protein assemblies. This structure then breaks down into three enzymes that work together to form the mature form of the virus, with current HIV treatments targeting all three enzymes. Informed by their findings, the researchers behind the discovery of HIV Pol’s structure believe that it could be targeted by a new generation of treatments.

As well as working on the understanding of the virus itself, researchers are investigating the way in which the immune system reacts to HIV. A study published by Scripps Research found that the innate immune system has a two-step response to determine the threat posed by HIV – firstly, by an essential protein, polyglutamine binding protein 1, recognising the outer shell of HIV and effectively creating an alert system, and then, secondly, cyclic GMP-AMP synthase detects the foreign presence to activate a molecular pathway to attack. The finding opens up the possibility of creating therapeutics that mimic the same response.

In terms of why some patients’ immune systems have difficulty targeting the virus, scientists at the University of Alberta found that patients with HIV were discovered to have killer T cells with very little to none of a protein known as CD73. The lack of this protein limited the killer T cells’ ability to identify and eliminate HIV-infected cells. Due to this discovery, the potential exists to research treatments that could aid T cells to migrate better to gain access to infected cells throughout the body.

Cutting edge therapeutics

With the complexity of HIV, there is hope that a new generation of treatments can match this with a more targeted approach to tackling the virus. The hope of being able to provide a functional or complete cure for AIDS is being raised by the prospect of utilising recent developments in the industry, including gene therapy and mRNA vaccines.

The mRNA vaccine approach is the most advanced and has been helped by the success seen in delivering a vaccine for COVID-19. Earlier this year, the US National Institute of Allergy and Infectious Disease (NIAID), announced that it had begun a phase 1 clinical trial evaluating three mRNA vaccines against HIV that were developed alongside Moderna. The clinical trials will look to determine the safety and immune response in patients of the different mRNA vaccines, with the technology designed to create a spike protein found on the surface of HIV that facilitates the virus’ entry into human cells. It is hoped that the vaccine would help the immune system recognise the virus upon infection and allow the body to more effectively combat its propagation through the body.

Gene therapies are another approach that has been validated with approvals in recent years. Now, this modality is being considered for its potential as a functional cure for HIV. Research being conducted at Oregon Health & Science University has led to funding from NIAID to study a single-dose gene therapy that could suppress HIV within patients living with the condition. The drug at the centre of the research is leronlimab, a monoclonal antibody being developed by CytoDyn, which has been found to prevent nonhuman primates from being infected with the monkey form of HIV.

As the next stage in the process, researchers will attempt to create a synthetic AAV vector to enable the long-term production of leronlimab inside the body, which could be created in muscle cells. Leronlimab blocks HIV from entering immune cells due to a surface protein called CCR5. The drug functions by mimicking a CCR5-deficient donor by occupying all available CCR5 molecules. If the treatment were to be successful, patients would no longer need to take antiretroviral therapy. Once created, the gene therapy will be tested on rhesus macaques that have been exposed to a monkey version of HIV, after which the nonhuman primates will be assessed for safety and efficacy.

Similar to the mRNA approach, the gene therapy treatment is still a number of years away from being approved for patients. However, the development of potential therapeutics using such emerging technologies offers hope that a viable, effective cure for HIV may be emerging on the horizon.