Adenoviruses The Good, the Bad, and the Ugly

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					                                 Adenoviruses: The Good, the Bad, and the Ugly
                                           By Arzhang Fallahi and David Kugler

Introduction:
       • History – Adenoviruses were discovered in 1953. About 47 different types have been
              identified since then, and about half of them are believed to cause human
              diseases. Infants and children are most commonly affected by adenoviruses.
              Adenovirus infections can occur throughout the year, but seem to be most
              common from fall to spring.
       • Characteristics and Structure –
              double-stranded DNA, icosahedron (20 triangular faces and 12 corners),
              nonenveloped.
       • Size – medium (70-90 nm)
       • Reproduction, Attack, and Replication –
              Virus attaches to receptor proteins on cell membrane; cell surrounds virus with its own membrane – the
              virus is now inside the cell. The virus shreds protein coat and breaks through the membrane, releasing
              DNA into the cell. DNA enters nucleus and takes over cell. Enzymes are synthesized, DNA is replicated,
              capsid proteins are synthesized, virions then mature. Cell lyses and releases new viruses.

The Ugly:
       • Diseases caused by Adenoviruses –
              Common cold, Pneumonia that doesn't respond to antibiotic therapy, Croup (inflammatory condition of the
              larynx and trachea), Bronchitis, Febrile respiratory disease (infection of respiratory tract that includes a
              fever), Conjunctivitis (pinkeye), Pharyngoconjunctival fever (infection of the lining of the eye and
              respiratory tract), Gastroenteritis (inflammation of the stomach and intestines), Encephalitis (inflammation
              of the brain), Acute mesenteric lymphadenitis (inflammation of lymph glands in the abdomen), Chronic
              interstitial fibrosis (abnormal growth of connective tissue between cells), Intussusception (a type of
              intestinal obstruction), Whooping cough syndrome when Bordetella pertussis (the bacterium that causes
              classic whooping cough) is not found.
       • Common Symptomology – cough, fever, runny nose, sore throat, watery eyes
       • Transmission – direct contact, oral-fecal, waterborne transmission (Getting the virus in the eyes by swimming
              in contaminated water, using contaminated eye solutions or instruments, wiping the eyes with
              contaminated towels, or rubbing the eyes with contaminated fingers).
       • Treatment – Treatment of adenovirus infections is usually supportive and aimed at relieving symptoms of the
              illness. Bed rest, drugs for fever/pain, topical corticosteroids for eye infections, hospitalization sometimes
              required for severe pneumonia.
       *Adenovirus infections are rarely fatal. Most patients recover fully.

The Bad:
      •     Instances of lethal Adenoviruses –
                o Gene Therapy Death Prompts Review of Adenovirus Vector (Science Article)
                             Jesse Gelsinger, a relatively fit 18-year-old with an inherited enzyme deficiency, died on 17
                             September, 4 days after doctors at Penn injected a genetically altered virus into his liver.
                             Gelsinger was the first patient in a gene therapy trial to die of the therapy itself
                             Vector used – a crippled form of adenovirus combined with a gene to control Gelsinger's
                             ammonia metabolism (the gene for ornithine-transcarbamylase, or OTC)
                             Invaded not just the intended target, the liver, but many other organs. This triggered an
                             "activation of innate immunity," followed by a "systemic inflammatory response."
                             Gelsinger's temperature shot up to 104.5 degrees Fahrenheit. He went into a coma on the
                             second day and was put on dialysis and then on a ventilator. His lungs filled with fluid. When
                             it became impossible to oxygenate his blood adequately, he died.
The Good:
      • Onyx Pharmaceuticals (ONYX-015)
           o ONYX-015 is a modified adenovirus that takes over the cells’ protein synthesis machinery, replicates,
               and then lyses to release its progeny.
           o In wild-type adenovirus, the early regulatory protein E1B-55kDa binds to and inactivates the host
               cell’s p53 protein to promote its own replication.
           o Without E1B-55-kDa, adenovirus is incapable of replication. However, researchers observed that an
               E1B-55-kDa mutant adenovirus (ONYX-015) could replication in and lyse p53-negative, but not p53-
               positive, human tumor cells.
       •   Traditional Cancer Therapy
               o surgery, chemotherapy, radiation therapy
               o The ability of tumor cells to develop chemotherapy resistance is a principal limitation of standard
                   anticancer drugs.
       •   p53 and cell apoptosis
               o P53 is with a class of genes known as tumor suppresser genes. It is located on chromosome 17 locus
                   ID 7157.
               o When DNA becomes damaged, elevated levels of p53 are made. The p53 then binds to DNA and
                   induces the DNA to make the mRNA that produces p21. This protein then, initiates a halt in the cell
                   cycle for the DNA to be repaired or signaling apoptosis.
               o Mutations in p53 are commonly seen in 45-70% of all cancers.
                            Clinical Trials – p53 mutant tumors underwent necrosis at a higher rate than did tumors with
                            a wild-type gene sequence (58% and 0% respectively). (Nature Medicine Article)
               o p53 function must be blocked in order to allow efficient virus replication
       •   E1A as a potent chemosensitizer
               o E1A gene expression is a potent chemosensitizer, which is independent of p53 in some models
                   (ONYX-015 expresses E1A in both p53-deficient and p53-functional cancer cells)
               o E1A expression does not chemosensitize normal, non-transformed cells.
               o May explain sensitization of p53-functional tumor cells, induction of high levels of p53 protein, or both.
       •   E1B protein and interaction with p53
               o 55-kDa protein binds and inactivates p53.
       •   Animations (normal and altered)
       •   Combined treatment applications
               o Cisplatin, 5-fluorouracil [5-FU] and Adenovirus
                            Clinical Trials – Combination treatment was well tolerated by patients; chemotherapy toxicity
                            was not demonstrably altered by concomitant viral therapy, and ONYX-015-related flu-like
                            symptoms were actually less severe than in prior studies with ONYX-015 as ‘monotherapy’.
                            Treatment caused an objective response (at least a 50% reduction in tumor size) in 19 cases,
                            with 8 complete responses. [Study out of 37 individuals]
                            Two of four chemotherapy-refractory tumors responded to subsequent therapy with ONYX-
                            015 plus the same chemotherapy they had been resistant to.
                            ONYX-015 combined with cisplatin and 5-FU was active as a method of local control in most
                            patients.
               o Future clinical trials may explore combinations of ONYX-015 by different routes of administration with
                   other chemotherapy regimens, radiation therapy, surgery and even other biological agents.

References:
       Internet:
       http://www.findarticles.com/cf_dls/g2601/0000/2601000024/p1/article.jhtml?term=adenovirus
       (Gale Encyclopedia of Medicine)
       http://www.findarticles.com/cf_dls/g2601/0003/2601000341/p1/article.jhtml
       (Gale Encyclopedia of Medicine)
       http://wawa.essortment.com/whatisadenovir_obf.htm

       Journal/Articles:
       “Gene Therapy Death Prompts Review of Adenovirus Vector.” Eliot Marshall. Science 1999. December 17; 286:
               2244-2245.
       “A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and
               5-fluorouracil in patients with recurrent head and neck cancer.” Khuri, Fadlo R., Nemunaitis, John.,
               Ganly, Ian., Arseneau, James., Tannock, Ian F., Romel, Larry., Gore, Martin., et. al. Nature Medicine.
               August 2000, Vol. 6 No. 8.
       “ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that
               can be augmented by standard chemotherapeutic agents.” Heise, Carla., Sampson-Johannes, Adam.,
               Williams, Angelica., McCormick, Frank., Von Hoff, Daniel D., and Kirn, David H. Nature Medicine. June
               1997 Vol. 3 No. 6.
       “Gene therapy scores against cancer.” Anderson, W. French. Nature Medicine. August 2000, Vol. 6 No. 8.