Virotherapy:-

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by

reprogramming viruses to treat diseases. There are three main branches of Virotherapy
Anti-cancer oncolytic viruses
Viral vectors for gene therapy
Viral immunotherapy
In a slightly different context, Virotherapy can also refer more broadly to the use of viruses to
treat certain medical conditions by killing pathogens.
1. Oncolytic viruses:-
Background:-
An oncolytic virus (OV) is a virus used to treat cancer due to its ability to specifically infect and
lyse cancer cells, while ideally leaving normal cells unharmed. A number of viruses, either
naturally occurring or developed through genetic engineering, are being investigated as oncolytic
agents for cancer treatment.
Oncolytic viruses are self-replicating, tumor selective and directly lyze cancer cells. They may
be tumor selective in wild-type or attenuated forms or may be engineered to provide tumor
selectivity. Naturally occurring oncolytic viruses include the double-stranded RNA reovirus and
single-stranded RNA Newcastle disease virus (NDV) and vesicular stomatitis virus (VSV). By
contrast, human DNA viruses, including adenoviruses, vaccinia and herpes simplex viruses
(HSV) have been genetically modified in a variety of ways to provide tumor selectivity.
Each virus has a specific cellular tropism that determines which tissues are preferentially
infected, and hence, what disease is caused. Rabies virus, for example, damages neurons,
hepatitis B virus damages hepatocytes, HIV damages helper T lymphocytes and influenza virus
damages airway epithelium.
A diverse range of mechanisms provide tumor specificity, including inactivation of antiviral
defenses , such as type I IFN responses in many cancer cells, viral deletions permitting
replication only in tumor cells that can substitute for viral defects, tumor-selective uptake via
upregulated or mutated receptors, and targeting to tumor promoters. In the majority of clinical
trials performed so far, oncolytic viruses have been administered via intratumoral injection.
Oncolytic viruses, the innate immune response & danger signals:-
The role of the innate immune response to cancer is double-edged. Oncolytic Virotherapy may
be immune modulatory via
Tumor cell death,
Production of endogenous danger signals,
The release of tumor-derived cytokines and
Direct effects upon cells of the innate immune system.
Evidence from preclinical models suggests that an early influx of immune cells, including
macrophages and natural killer (NK) cells, occurs in response to tumor viral therapy. Dendritic
cells (DC), the prime antigen presenting cells and a component of the innate immune response
are critical for the subsequent generation of antigen-specific or adaptive immune responses.
Tumor cell death:-
Virally induced cell death would be expected to enhance the availability of tumor-associated
antigens (TAA) for uptake by Dendritic cells (DC). Indeed, viral infection of tumors has been
reported to enhance the phagocytosis of tumor-derived material. The immunogenicity of tumors
has been reported not to be affected by whether tumor cells are alive, apoptotic or necrotic.
Tumor-derived cytokines:-
An array of cytokines provides costimulation for T-cell responses; while by contrast, tumor
derived cytokines, including TGF- and IL-10, have immunosuppressive properties. In addition,
the tumor-derived proinflammatory cytokines VEGF, TNF-and several chemokines have been
linked to promotion of tumor growth. Oncolytic viral infection is likely to alter the balance of
cytokines produced and the nature of the subsequent immune response. It was investigated the
release of cytokines following infection of melanoma cells with reovirus, a naturally occurring
double-stranded RNA virus currently in clinical trials. Reovirus was found to induce secretion of
IL-8, RANTES and MIP-1/, which play a role in the recruitment of DC, neutrophils and
monocytes and of IL-6, which can inhibit the immunosuppressive function of Treg cells.
DC & the response to viral infection:-
The immune system is adept at pathogen recognition and a host of receptors specific for
pathogen-associated molecular patterns, including the toll-like receptors (TLR), have been
identified. Innate viral recognition can center around viral nucleic acids or viral proteins. DC
play a critical role in the early innate immune responses, reciprocally interacting with other
innate immune cells, including NK cells.
Oncolytic viruses & adaptive antitumor immunity:-
An adaptive antitumor immune response requires activation of cytotoxic CD-8 T cells by DC
presenting tumor antigen on MHC class I molecules. The presentation of exogenous antigen in a
MHC class I context is termed cross-presentation. Critically, virally infected cells have been
shown to be superior at delivering non-viral antigen for cross-presentation and cross-priming
adaptive immune responses in vivo. Intriguingly, recent work has defined a role for TLR-4
receptor ligands (bacterially derived lipopolysaccharide) in enhancing cross-presentation; a
similar effect of viral as opposed to bacterial TLR ligands has yet to be explored.
Future directions: combination therapy:-
Combination therapy may be the optimal context in which to exploit the immunotherapeutic
potential of oncolytic viruses. A rationale exists for combination with existing immunotherapy
strategies, along with conventional therapy.
2. Viral vectors for gene therapy:-
Genetic manipulation of somatic cells of individuals is known as gene therapy. Viruses are
routinely used in the genetic modification of model organisms for research purposes. The
production of transgenic plants and animals in agriculture has also been established, but germ-
line modification of humans has not been attempted for technical and ethical reasons.
The key element of gene therapy is the introduction of functioning genes into the cells of a
human patient, to express desired functions or to correct defective or non-operational genes
within those cells. Delivery systems must be able to introduce DNA into appropriate target cells.
I. Ex vivo gene therapy involves removal of the cells from the body, followed by their
treatment and reintroduction.
II. In vivo gene therapy is more challenging, and involves targeting of target cells within the
body.
Examples of current approaches include the lung cells of cystic fibrosis sufferers where a defect
in an ion transport protein produces excess mucus and damages the lung surface, and the
hematopoietic cells of sufferers from various forms of severe combined immunodeficiency
(SCID), which causes profound immunosuppression by preventing the production of
lymphocytes.
Virus vector systems:-
Virus vectors are used for ex vivo gene therapy, but are particularly useful where the target cells
are in less accessible areas of the body. Viruses provide highly efficient systems for getting
foreign nucleic acid into cells, and they are also highly suited to protecting a nucleic acid while
transporting it to the required area of the body.
Adenoviruses are widely used as vectors, and can be engineered both to enhance specificity and
to minimize unwanted effects.