VI04_Editorial ARI 9 August 2017 14:28

The Good That Viruses Do

Mario Mietzsch and Mavis Agbandje-McKenna
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Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32611;
email: mckenna@ufl.edu
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It is astonishing that with our more than thirty-five combined years of working in the field of
virology, we continue to read on a regular basis about novel emerging viruses infecting species
from all three domains of life. The focus of our research is on single-stranded DNA viruses. Even
for this apparently small group of viruses, many new members are identified each year that need
to be characterized, providing seemingly endless opportunities for new research directions. In-
deed, studying these new viruses does not end with characterization of their physical properties or
disease-causing phenotypes, because many have the potential to be developed into useful biologics
with therapeutic benefits to humans. Our experience as virologists suggests that the use of “good”
viruses is common practice. If a survey were to ask nonvirologists for their opinions about viruses,
the word “good” would be unlikely to arise. Instead, words such as “disease,” “infection,” “suf-
fering,” or “life-threatening” would likely dominate, as people primarily think of viruses such as
HIV, Ebola virus, Zika virus, influenza virus, or whatever new outbreak is in the news. However,
as we are now finding out, not all viruses are detrimental to human health. In fact, some viruses
have beneficial properties for their hosts in a symbiotic relationship (1), while other natural and
laboratory-modified viruses can be used to target and kill cancer cells, to treat a variety of genetic
diseases as gene and cell therapy tools, or to serve as vaccines or vaccine delivery agents. The
ability to treat diseases using viruses, often referred to as virotherapy, has become the subject of
intensive research in recent years.
Cancer is one of the leading causes of death worldwide. According to the World Health Orga-
nization, about 8.8 million people died from cancer in 2015. Conventional treatment of cancer is
based primarily on chemotherapy, radiation therapy, and surgery. Although these therapies have
increased patient survival rates, their efficacy is often limited depending on the type of cancer
being treated. In addition, significant side effects occur because noncancerous cells are also tar-
geted by these treatment modalities. Recurrence after successful treatment is also of concern. An
emerging field in cancer therapy comprises alternative therapies that use viruses to kill cancer cells
selectively. The idea for this approach came through early observations of cancer regression in
patients suffering from unrelated viral infections (2). In the past two decades, viruses from a variety
of different families (e.g., Adenoviridae, Herpesviridae, Rhabdoviridae, Parvoviridae, Picornaviridae,
Reoviridae, and Poxviridae) have been studied for their potential use as anticancer agents (3). Due to
their tropism for tumors and their ability to replicate selectively in and eventually lyse cancer cells

https://doi.org/10.1146/annurev-vi-04-071217-100011

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without harming noncancerous cells, they are referred to as oncolytic viruses. Currently, multiple
phase I to phase III clinical trials are ongoing for the treatment of various cancer types, including
hepatocellular carcinoma, glioblastoma multiforme, colorectal cancer, and cancers of the lung,
breast, prostate, pancreas, bladder, and ovaries (4). In 2015, the first oncolytic virus therapy based
on a herpesvirus was approved by the US Food and Drug Administration and European Medicines
Agency for the treatment of melanoma lesions in the skin and lymph nodes (5). In the near future
we expect to see that the successful completion of several clinical trials will lead to the approval
of additional oncolytic virus therapies.
In contrast to oncolytic virus therapies, where the treatment is based on virus replication and
cell death, nonreplicating viruses are being utilized as vectors for corrective gene delivery. The
goal of virus-mediated gene therapy is the delivery and expression of therapeutic genes to desired
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target cells to restore the function of a defective gene for the treatment of monogenetic disor-
ders. Viral gene therapy uses the natural capacity of virus particles to protect the encapsidated
nucleic acid from degradation and to deliver the DNA to the nucleus. For the ideal gene therapy
vector the viral wild-type genome is almost entirely substituted with a recombinant transgene
Annu. Rev. Virol. 2017.4:iii-v. Downloaded from www.annualreviews.org

expression cassette. This aspect is a major difference compared with the oncolytic viruses used
in anticancer therapies, which encode many viral genes. In hundreds of ongoing clinical trials,
the most commonly used vectors for gene therapy are adenoviruses, retroviruses/lentiviruses, and
adeno-associated viruses (AAVs) (6). Each system has its pros and cons that must be considered
prior to use to ensure efficient gene delivery and expression for clinical success. Recent successes in
various clinical trials have been achieved especially using lentiviral and AAV vectors (6). Lentiviral
vectors are primarily used for ex vivo hematopoietic gene delivery, where patient cells are re-
moved and transduced with the viral vector, resulting in modified cells that can be transplanted
back to the patient after thorough screening of the transplant. The pre-administration screening
allows the identification of mutagenic integration sites of proviral genomes in the cellular genome
of the transplant. These screenings were incorporated into clinical trial design after the discov-
ery of insertional oncogenesis leading to T cell leukemia in patients undergoing retroviral gene
therapy. In contrast, AAV vectors are used mainly for in vivo gene therapy applications, where
viral vector particles are injected intravenously, intramuscularly, intracranially, intravitreally, or
subretinally, depending on the desired target cells. Notably, an AAV1 vector for the treatment of
lipoprotein lipase deficiency was approved as the first viral gene therapy medical product in the
Western world by the European Medicines Agency in 2012 (7). This approval led to a massive
surge of industry interest and the growth of the AAV biotechnology field, including the raising
of $2 billion by just ten companies in 2015 for the development of AAV gene therapies. Another
example of a successfully completed AAV vector clinical trial involves an AAV8 vector expressing
human factor IX for the treatment of hemophilia B. A single injection of these AAV particles
resulted in a more than 90% reduction in the number of bleeding episodes in study participants
over a period of more than three years, with no toxic effects (8). One downside is that AAV gene
therapy is currently the most expensive therapeutic, at ∼$1 million per treatment. Certainly, con-
tinued effort is required to make it affordable. Another problem with AAV gene therapy is the
potential for immune responses against the virus capsid as well as the therapeutic gene products
that are produced. Ten to fifteen years ago, it was believed that AAVs did not elicit an immune
response. However, applications in large animals, nonhuman primates, and humans have since
proved that this is untrue. Thus, in order to maintain the expression of the therapeutic protein,
different strategies have been developed to avoid or suppress these immune responses (9).
In gene therapy scenarios, it is important to avoid immune responses to the virus capsid and
transgene product. In contrast, for viral vaccines, elicitation of immune responses, including the
generation of neutralizing antibodies, is the goal. To induce a protective immune response, patients

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are injected with an attenuated or inactivated virus or with specific viral antigens. For patients with
an immune deficiency disorder, passive immunization by direct administration of antibodies can
be done. However, this immunity is temporary, lasting only for a few weeks or months. Therefore,
gene therapy vectors have been developed that express broadly neutralizing antibodies that can
be used for the long-term treatment of HIV and influenza as well as for cancer therapy (10).
Some of the viruses infecting humans are indeed capable of causing severe and often lethal
diseases, but other viruses can be manipulated to be beneficial to human health. These viruses
offer the potential to cure cancer, correct genetic disorders, or fight pathogenic viral infections. In
addition, viruses are used in many genetic studies to determine molecular mechanisms, are used
as insecticides, and have been reported to increase drought tolerance in some plants. Virologists
must strive to downplay the “bad” reputation of viruses and promote dialogue on the many “good”
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things that they can do.

LITERATURE CITED
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1. Roossinck MJ. 2011. The good viruses: viral mutualistic symbioses. Nat. Rev. Microbiol. 9:99–108
2. Kelly E, Russell SJ. 2007. History of oncolytic viruses: genesis to genetic engineering. Mol. Ther. 15:651–59
3. Bell J, McFadden G. 2014. Viruses for tumor therapy. Cell Host Microbe 15:260–65
4. Choi A, O’Leary M, Fong Y, Chen N. 2016. From benchtop to bedside: a review of oncolytic virotherapy.
Biomedicines 4:18
5. Pol J, Kroemer G, Galluzzi L. 2016. First oncolytic virus approved for melanoma immunotherapy.
Oncoimmunology 5:e1115641
6. Kotterman MA, Chalberg TW, Schaffer DV. 2015. Viral vectors for gene therapy: translational and
clinical outlook. Annu. Rev. Biomed. Eng. 17:63–89
7. Kastelein JJ, Ross CJ, Hayden MR. 2013. From mutation identification to therapy: discovery and origins
of the first approved gene therapy in the Western world. Hum. Gene Ther. 24:472–78
8. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, et al. 2014. Long-term safety and
efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371:1994–2004
9. Nayak S, Herzog RW. 2010. Progress and prospects: immune responses to viral vectors. Gene Ther.
17:295–304
10. Schnepp BC, Johnson PR. 2014. Vector-mediated in vivo antibody expression. Microbiol. Spectr. 2:AID-
0016-2014

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Annual Review
of Virology

Contents Volume 4, 2017

History
Finding, Conducting, and Nurturing Science: A Virologist’s Memoir
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Anna Marie (Ann) Skalka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1

Ecology and Evolution

Annu. Rev. Virol. 2017.4:iii-v. Downloaded from www.annualreviews.org

The Discovery, Mechanisms, and Evolutionary Impact

of Anti-CRISPRs
Adair L. Borges, Alan R. Davidson, and Joseph Bondy-Denomy p p p p p p p p p p p p p p p p p p p p p p p p p p37
Giant Viruses of Amoebae: A Journey Through Innovative Research
and Paradigm Changes
Philippe Colson, Bernard La Scola, and Didier Raoult p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p61
The Distribution, Evolution, and Roles of Gene Transfer Agents
in Prokaryotic Genetic Exchange
Andrew S. Lang, Alexander B. Westbye, and J. Thomas Beatty p p p p p p p p p p p p p p p p p p p p p p p p p p87
Constraints, Drivers, and Implications of Influenza
A Virus Reassortment
Anice C. Lowen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Symbiosis: Viruses as Intimate Partners
Marilyn J. Roossinck and Edelio R. Bazán p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 123
New World Arenavirus Biology
Nicolás Sarute and Susan R. Ross p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141
Viruses with Circular Single-Stranded DNA Genomes
Are Everywhere!
L.M. Shulman and I. Davidson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 159
The Bridges and Blockades to Evolutionary Convergence on the Road
to Predicting Chikungunya Virus Evolution
Marco Vignuzzi and Stephen Higgs p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 181
Viruses in Soil Ecosystems: An Unknown Quantity Within an
Unexplored Territory
Kurt E. Williamson, Jeffry J. Fuhrmann, K. Eric Wommack,
and Mark Radosevich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
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Genome Replication, Regulation of Gene Expression, and Biosynthesis

Enzymes and Enzyme Activity Encoded by Nonenveloped Viruses
Kimi Azad, Manidipa Banerjee, and John E. Johnson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221
Making Sense of Multifunctional Proteins: Human Immunodeficiency
Virus Type 1 Accessory and Regulatory Proteins and Connections to
Transcription
Tyler B. Faust, Jennifer M. Binning, John D. Gross, and Alan D. Frankel p p p p p p p p p p p 241
The Molecular Basis for Human Immunodeficiency Virus Latency
Uri Mbonye and Jonathan Karn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
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Assembly and Egress

Electron Cryomicroscopy of Viruses at Near-Atomic Resolutions
Annu. Rev. Virol. 2017.4:iii-v. Downloaded from www.annualreviews.org

Jason T. Kaelber, Corey F. Hryc, and Wah Chiu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287

A Consensus View of ESCRT-Mediated Human Immunodeficiency
Virus Type 1 Abscission
J. Lippincott-Schwartz, E.O. Freed, and S.B. van Engelenburg p p p p p p p p p p p p p p p p p p p p p p p p 309

Pathogenesis
Astrovirus Biology and Pathogenesis
Valerie Cortez, Victoria A. Meliopoulos, Erik A. Karlsson, Virginia Hargest,
Cydney Johnson, and Stacey Schultz-Cherry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 327
Progressive Multifocal Leukoencephalopathy: Endemic Viruses
and Lethal Brain Disease
Sheila A. Haley and Walter J. Atwood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 349
Defensins in Viral Infection and Pathogenesis
Mayumi K. Holly, Karina Diaz, and Jason G. Smith p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Humanized Mouse Models for Human Immunodeficiency
Virus Infection
Matthew D. Marsden and Jerome A. Zack p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
Immunopathology of Chikungunya Virus Infection: Lessons Learned
from Patients and Animal Models
Lisa F.P. Ng p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Cassava Mosaic and Brown Streak Diseases: Current Perspectives
and Beyond
Chrissie Rey and Hervé Vanderschuren p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429
Phage Tail–Like Bacteriocins
Dean Scholl p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 453
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Antivirals
Fate-Regulating Circuits in Viruses: From Discovery
to New Therapy Targets
Anand Pai and Leor S. Weinberger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469

Viral Vectors and Therapeutics

Engineered Expression of Broadly Neutralizing Antibodies Against
Human Immunodeficiency Virus
Maham Ahmad, Osama M. Ahmed, Bruce Schnepp, and Philip R. Johnson p p p p p p p p p p p 491
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Overcoming the Host Immune Response to Adeno-Associated Virus

Gene Delivery Vectors: The Race Between Clearance, Tolerance,
Neutralization, and Escape
Annu. Rev. Virol. 2017.4:iii-v. Downloaded from www.annualreviews.org

Federico Mingozzi and Katherine A. High p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511

Errata
An online log of corrections to Annual Review of Virology articles may be found at
http://www.annualreviews.org/errata/virology