phage

by Gertrud U. Rey

The ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell can be exploited for various purposes. For example, viruses can be used as vectors for delivering vaccines, healthy copies of defective genes (i.e., for “gene therapy”), and therapeutic drugs to specific cells.

Several SARS-CoV-2 vaccines, including those made by AstraZeneca and Johnson & Johnson, consist of a “vector virus” (an adenovirus) that contains a gene for the SARS-CoV-2 spike protein. Upon injection into a vaccine recipient, the vector virus should enter cells and serve as a code for host proteins to synthesize the encoded spike protein. Genes that regulate replication of the vector virus are removed to ensure that the vector itself cannot cause an infection in human cells. Other genes not needed for purposes of vaccine delivery are also typically removed to create more room inside the vector for the inserted antigen gene. Adenoviruses are particularly suitable for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate segments of foreign DNA and because they infect most cell types without integrating into the host genome. However, poxviruses, retroviruses, vesicular stomatitis virus, and other viruses can also be used for vaccine delivery. As of today, six viral-vectored vaccines have been authorized for use in humans: four SARS-CoV-2 vaccines (two of which were previously described here and here) and two Ebola virus vaccines.

Viruses may also serve as vectors for targeted gene therapy to treat genetic disorders caused by mutations in the sequence of a person’s DNA. By replacing the mutated, non-functional portion of DNA with its healthy counterpart, the function of the defective gene could potentially be restored. Some viruses, like retroviruses, already insert their genetic material into the host genome as part of their replication cycle, making them suitable for delivering such functional genes to target cells. Recent advances in technology may even allow for the delivery of CRISPR-mediated gene editing tools to edit the target genome in the cell by excising the defective gene and replacing it with a functional version. One such targeted therapy aimed at treating genetic muscle disease by specifically targeting muscle cells was recently discussed on TWiV 812. Another exemplary gene therapy method for potentially deleting integrated HIV-1 from the genomes of infected individuals using CRISPR technology was described in a previous post.

A similar vector approach can also be used for cell-specific delivery of therapeutic drugs. For example, replication-incompetent viruses (viruses that have been engineered so they can’t replicate) can be further modified. These modifications may allow the viruses to specifically target dividing tumor cells or cells that display surface proteins that are unique to cancer cells, and deliver chemotherapeutic drugs only to those cells. Alternatively, replication-competent viruses can be manipulated to directly target and kill cancer cells in a mechanism known as oncolytic virotherapy. An example of this mechanism described previously involves a herpes simplex virus engineered to target a receptor that is practically absent in healthy brain cells, but is specifically expressed on glioblastoma multiforme tumor cells. The engineered virus also encodes a gene for a cytokine that increases the effectiveness of oncolytic viruses by recruiting cytotoxic T lymphocytes, which cause the tumor cells to burst. An accumulating body of evidence suggests that the cancer-specific antigens that emerge from burst cancer cells may also trigger additional downstream immune responses, further enhancing the potency of oncolytic viruses.

Considering that we are on the brink of a major antibiotic resistance crisis, viruses may just come to our rescue in this regard as well. Bacteriophages (“phages” for short) are viruses that only infect bacteria, and as it turns out, they can be used to treat pathogenic bacterial infections. There are numerous potential advantages to phage therapy compared to traditional antibiotic therapy. Phages are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria. They are also more specific than antibiotics, and this specificity leads to reduced impact on commensal bacteria, which are typically obliterated by conventional antibiotics. Unlike most antibiotics, phages are capable of disrupting bacterial biofilms, and their use would lead to reduced incidence of opportunistic infections and reduced toxic effects of bacterial infection. Although bacteria can become resistant to phages, phages can likewise evolve to overcome this resistance, making bacterial resistance to phages less of a challenge than their resistance to antibiotics. Furthermore, scientists have found that the efficacy of phage therapy can be improved by combining phages with an antibiotic treatment regimen, or by combining several phages in a “phage cocktail.” In a highly publicized phage therapy success story, infectious disease epidemiologist Steffanie Strathdee describes how she recruited the help of an international team of physicians to cure her husband of a life-threatening multi-drug-resistant Acinetobacter baumanii infection using an intravenous phage therapy cocktail.

Phages can also be used as an alternative energy source by powering the electrodes in batteries. As repeatedly demonstrated by materials scientist Angela Belcher at MIT, biological scaffolds composed of M13 phages that display the negatively charged peptide sequence glutamate-glutamate-alanine-glutamate (E-E-A-E) inevitably attract nickel phosphide molecules, and the resulting nanostructures can be used directly as freestanding negative electrodes in batteries. These “virus batteries” have multiple advantages over traditional batteries. They are more environmentally friendly because they’re made from non-toxic materials. Their synthesis requires relatively little equipment, so they are inexpensive to produce. They are lightweight and flexible and can thus be woven into fabrics, which makes them suitable for military clothing. They also have higher conductivity than conventional lithium-ion batteries, making them extremely useful for portable electronics, medical implants, and various aerospace applications. It is even possible that they could one day be used to power electric cars.

The examples described so far are ones in which people have capitalized on virus functions for the benefit of humans. However, viruses have other benefits that just relate to their natural functions. For instance, phages are also an essential component of our environment, where they help control pests and recycle nutrients. If phages didn’t exist, some bacterial populations would explode and outcompete other populations, causing them to disappear completely. This imbalance would be especially disastrous in the oceans, where microbes make up more than 70% of the total biomass. Phages kill a large portion of oceanic bacteria every day, allowing the organic molecules released from the dead bacterial cells to be recycled as nutrients for other organisms. Perhaps the most important organisms to benefit from these recycled nutrients are microscopic plants called phytoplankton, which produce oxygen by removing carbon dioxide from the atmosphere. In fact, phytoplankton are a crucial element of the global carbon cycle and one of the largest contributors to our atmospheric oxygen. This means that without viruses, we would not have air to breathe.

Viruses are deeply integrated in life on earth, and their functions in sustaining environmental equilibrium and our ongoing survival are too numerous to describe in a single blog post. Moreover, our current appreciation of what can be accomplished using viruses is cursory, at best. Future research will lead to a deeper understanding of how viruses can be utilized to do more good.

[This post was written in honor of Virus Appreciation Day, which occurs annually on October 3]