How Can Viruses Be Harnessed for Good?
Viruses are a constant threat to human health, but scientists are finding new ways to use them to combat disease.
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Viruses are the agents of many diseases, causing serious epidemics and pandemics throughout human history. Since their existence was first proposed at the end of the 19th century, we have traditionally thought of viruses as a burden that cause disease. Now, the traits that make viruses difficult to fight are being harnessed to tackle diseases that medicines can’t, helping fight cancer, genetic disorders and even infectious diseases.
Viruses are much simpler than bacteria or fungi, often only encoding a handful of genes on an RNA or DNA genome, which is encased in a protein core or lipid envelope (or both). To reproduce, viruses hijack the host cell’s machinery and deliver their genetic material into the cell. These new virus particles are either released in such great numbers that they lyse (i.e., burst) the host cell or are released in lower numbers to maintain longer-term infection, leading to clearance or persistence.
In light of the growing risk of antibiotic resistance, scientists have revisited the century-old practice of phage therapy, which harnesses viruses to attack disease-causing bacteria. However, utilizing human viruses for human disease is a much newer concept, yet advances in molecular biology, genetic engineering and virology are helping accelerate progress.
What do viruses offer to medicine?
The unique replication cycle of viruses offers several new opportunities for fighting disease. Broadly, the applications of viral interventions can be broken down into three areas: gene therapies, which primarily address genetic disorders; oncolytics, which use viruses to destroy cancerous cells; and immunotherapies, which stimulate immunity against diseases.
Gene therapies
Viruses can be engineered to deliver specific nucleic acids to cells to repair or replace defective genes, express a protein or switch disease-related genes on or off. This is known as gene therapy. Several gene therapies have already been approved in treating inherited diseases, viral diseases and cancers that cannot be managed by drugs.
Most gene therapies use viral vectors to deliver nucleic acids to cells because they are tunable to tissue or cell type and are efficient at protecting their cargo from degradation until it reaches the nucleus of cells. The main viral vectors currently in use are lentiviruses and adeno-associated viruses (AAVs), which each have unique characteristics that suit them for specific applications.
Lentiviruses
Lentiviruses are primarily used ex vivo to modify cells from a patient before reintroduction into the body. Lentiviruses are retroviruses, which include the HIV-1 and HIV-2 viruses, and are characterized by RNA genomes being reverse-transcribed to DNA and integrated into the host genome (transduction). This trait is extremely useful for stably modifying cells and passing on gene modifications to daughter cells as the treated cells divide.
Typical lentivirus therapies include modifications of a patient’s hematopoietic stem cells (HSCs) or T cells to endow a new trait that may replace a faulty gene or introduce a new receptor to recognize cancerous cells.
Lentiviral gene transfer into CD34+ HSCs has been used to treat several genetic diseases, including delivery of the common gamma chain (γc) to restore immune function in SCID-X1 patients, delivery of wildtype ABCD1 in X-linked adrenoleukodystrophy and transfer of the β-globin gene to β-thalassaemia patients to eliminate the need for transfusion. Each of these treatments is based on the transfer of a healthy gene to progenitor cells, which are reintroduced to the body and express the healthy gene to restore function.
Lentiviruses have also seen clinical success in generating CAR T cells and cancer vaccines. Chimeric antigen receptor (CAR) T-cell therapies involve the introduction of chimeric receptors (via lentiviral gene transfer) into a patient’s harvested T cells, so that they recognize cancerous cells. The first CAR T-cell therapy was approved in 2017 for acute lymphoblastic leukemia in children, followed by approval for the treatment of adults with blood cancers like non-Hodgkin lymphoma and multiple myeloma.
Cancer vaccines that utilize lentiviral vectors have also been investigated. Dendritic cells loaded with peptide from a tumor antigen can be used as a vaccine against cancers expressing that antigen. One such dendritic cell vaccine, Sipuleucel-T, has been approved by the US Food and Drug Administration (FDA) since 2019 as a prostate cancer therapy.
Adenoviruses and adeno-associated viruses
Adenoviruses (AdVs) and AAVs offer alternatives to lentiviruses as vectors in gene therapy, often being deployed in vivo to tackle disease. The first gene therapy ever to be approved for commercial use is GendicineTM, an Ad5 vector carrying functional p53 to repair the tumor suppression pathway. Gendicine was first approved in China in 2003 and has since been used to treat head and neck cancers alongside chemotherapy.
AAVs have been used to greater effect in gene therapy owing to their lower chance of immune clearance or side effects versus AdVs. AAVs are relatively small and encode their genome on a single strand of DNA, less than 5 kb in length, versus 36 kb in AdVs. Recombinant AAVs (rAAVs) allow for fine-tuning of cell specificity and payload delivery, and thus far, seven rAAV-based gene therapies have been approved globally. The first of these was GlyberaTM, which was approved in Europe in 2013 to treat lipoprotein lipase deficiency but has now been withdrawn from the market. This was followed by LuxturnaTM, which was approved by the FDA in 2017 to treat an inherited eye disorder that leads to blindness in infants.
Figure 1: Approved gene therapy products and delivery platforms throughout the past 20 years. This figure is adapted from Wang et al., 2024. Credit: Technology Networks.
Oncolytics
The ability of viruses to recognize and kill cancer cells has been known for almost a century, however, a lack of understanding of virology and tumor biology meant that oncolytic virus therapies were never a viable treatment option. In the last two decades, enhanced understanding and a much-improved toolkit in molecular biology and virology have renewed the scientific community’s interest in oncolytic viruses.
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The outcomes of viral infections are often variable, but fundamentally, immune clearance of infected cells or cell death is often common. Both outcomes lead to the death of the cell, which would be desirable in the context of a cancer cell or tumor. Oncolytic viruses can be naturally occurring or engineered to selectively target and destroy cancer cells, establishing lytic infection in tumors. Lytic infection then releases tumor antigens, which stimulate an anti-tumor immune response.
To date, four oncolytic viruses have been approved as cancer treatments, although only talimogene laherparepvec (T-VEC) is widely approved. T-VEC is a modified Herpes virus that is approved to treat melanomas by selectively replicating in tumors without being pathogenic to healthy cells. T-VEC is additionally modified to allow the presentation of tumor-derived antigens to the immune system and enhance the local immune response, which assists in anti-tumor immunity. Beyond T-VEC, another Herpes virus-based treatment, Teserpaturev, has been approved for the treatment of gliomas in Japan.
AdVs have also been deployed as oncolytic treatments. The first of these to be approved in 2005 was H101, for the treatment of head and neck cancers alongside chemotherapy. In 2022, the FDA approved Nadofaragene firadenovec for the treatment of bladder cancers, which otherwise carry extremely low response rates to chemotherapy and very poor survival rates.
Future directions
After decades of research into viruses so that we can reduce their impact on the world, scientists now have enough of an understanding of viruses that they can be redirected to fight the diseases that drugs cannot.
Gene therapies, which largely rely on viruses to efficiently deliver genetic material to a target cell, have improved the outlook of many patients with debilitating genetic diseases who otherwise had no treatment options. Cancers with poor survival or those that had become resistant to conventional treatment are now in the sights of CAR T-cell therapies and cancer vaccines. Oncolytic viruses also offer new avenues to fight cancers that no longer respond to treatment or cannot be removed surgically.
Overall, the landscape for harnessing viruses in our fight against disease is looking promising. The exponential growth in the number of clinical trials regarding gene therapies and oncolytic viruses shows great promise in these fields, and the growing number of approvals for these treatments shows that regulatory approval is possible.
Some logistical issues remain with the scale-up of production of many vectors and oncolytic viruses, providing a barrier to large-scale adoption. The long-term effects of these treatments are also unclear, but as this research moves out of its infancy, it is likely that any unforeseen effects will become clear and can be mitigated in future therapies.
