Viruses and cancer
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Viruses and cancer. Viruses and cancer. Brief background on cell cycle factors Rb and E2F example. Enquist et al., Principles of Virology, ASM, 2004. Example: DNA damage during G1 P53 recognizes DNA damage and activates P21 (p53 recognizes certain types of DNA mismatches)

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Viruses and cancer

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Viruses and cancer

Viruses and cancer


Viruses and cancer

Viruses and cancer

Brief background on cell cycle factors

Rb and E2F example

Enquist et al., Principles of Virology, ASM, 2004

Example: DNA damage during G1

P53 recognizes DNA damage and activates P21 (p53 recognizes certain types of DNA mismatches)

P21 binds and inactivates the cyclin-CDK complex which has already begun to be produced in response to different signals

DNA repaired, p53 decreases, P21 no longer blocks cyclin-CDK, cell cycle progression

P53 act as a checkpoint controller to stop cell-cycle progression


Viruses and cancer

Inactivation of p53 by papillomavirus proteins

HPV

E6 protein

Enquist et al., Principles of Virology, ASM, 2004


Viruses and cancer

HPV E5 protein

increases EGF

receptor concentration

E5 binds vacuolar ATPase and

inhibits acidification of endosomes

Enquist et al., Principles of Virology, ASM, 2004


Viruses and cancer

E7 protein of HPV

Similar proteins of other viruses

these proteins bind Rb complex and prevent Rb from

negatively regulating E2f

SV40 virus LT (Large T antigen)

Adenovirus E1a protein

Adenovirus not oncogenic in humans (yes in hamsters)

In humans the virus infection & release kills cells, but a defective virus might be oncogenic in humans

Enquist et al., Principles of Virology, ASM, 2004

SV40 LT disassembly of Rb-E2f complex


Antiviral treatment strategies chapter 44

Antiviral Treatment Strategies (Chapter 44)

  • Inhibitors of viral replication

    • every step in viral replication is potentially a target

    • targeting host cell functions is generally not feasible (toxicity)


Agents developed by an empirical approach

Agents developed by an empirical approach

  • Interferons

    • natural products discovered in 1957

    • Interferons assist the immune response

      • inhibit viral replication within host cells

      • activate natural killer cells and macrophages

      • increase antigen presentation to lymphocytes

      • induce resistance of host cells to viral infection.

    • Type I interferons

      • Interferon-(produced by leukocytes; induced by viruses)

      • Interferon-(produced by fibroblasts & epithelial cells; induced by viruses)

    • Type II interferon

      • Interferon-(induced by antigens and mitogens)


Effects of interferon therapy

Effects of interferon therapy

  • Fatigue

  • Fever

  • Myalgias

  • Bone marrow suppression

  • Neuropsychiatric problems

  • Treatment for hepatitis C Virus (HCV) infection

  • Formerly used for HBV


Ribavirin

Ribavirin

  • Purine nucleoside analog

  • Inhibits many RNA viruses and some DNA viruses

    • Influenza A and B

    • Measles

    • Respiratory Syncytial Virus

  • Several different mechanisms of action

    • Inhibits viral polymerases

    • Reduces GTP levels

    • Impairs 5’ capping of viral mRNAs

  • Lack of potency at nontoxic levels


Steps in virus replication targeted by current drugs and drugs in development

Steps in virus replication targeted by current drugs and drugs in development


Viruses and cancer

Virus entry

Enfuvitide - HIV fusion inhibitor

Binds to gp41 region that folds back onto itself

Prevents fusion of membranes

Very specific to HIV


Viruses and cancer

Virus entry

  • used to prevent influenza infections

  • blocks penetration and uncoating of influenza A virus

75% effective if given prior to viral exposure

50% effective if given after 1st signs of infection

Rimantadine = analog


Viruses and cancer

Amantadine and rimantadine affect M2’s function as an ion channel

Following endocytosis, acidification of endosomes occurs

Then M2 can function as ion channel

Acidification within virion drives viral disassembly


Viruses and cancer

Viral genome replication

Acyclovir - result of rational drug design

targeting herpesviruses

involved in DNA synthesis and function

Viral TK much more efficient than cellular TK in this reaction (so drug is specific to infected cells)

However, acyclovir has no effect on latency


Viruses and cancer

Comparison of intravenous acyclovir and placebo for inhibition of virus shedding in immunocompetent individuals with first episode of genital herpes

Comparison of oral acyclivir (blue) and placebo (red) for suppression of recurrent genital herpes.


Viruses and cancer

Viral genome replication

inhibits herpes virus enzymes

involved in DNA and RNA

synthesis and function

inhibits herpes

virus DNA

polymerase

Directly inhibits

herpesvirus and

cytomegalovirus

DNA polymerase

Ganciclovir is effective against CMV compared to acyclovir, although it is also more toxic (cellular TK uses drug better too).


Viruses and cancer

Cidofovir is a relatively broad-spectrum anti-DNA virus drug

inhibits

viral DNA

polymerase

papovaviruses,

adenoviruses,

herpesviruses

iridoviruses,

and poxviruses


Nucleoside reverse transcriptase inhibitors nrti

Anti-HIV drugs:

nucleoside reverse transcriptase inhibitors (NRTI)

nonnucleoside reverse transcriptase inhibitors (NNRTI)

Delaviridine

Efavirenz

Nevirapine


Viruses and cancer

Anti-HIV drugs: Protease inhibitors

Peptidomimetic inhibitors

Ritonavir

But unexpected activity:

Cytochrome P450 3A4 inhibitor

Saquinavir

HAART = highly active antiretroviral therapy

at least 3 drugs in combination

2 nucleoside inhibitors plus a NNRTI or a protease inhibitor


Virus release

Virus release

Neuraminidase inhibitors - influenza virus

neuraminidase (NA)

release of virus from envelope

cleaves sialic acid (NA has enzymatic activity)

Inhibitors prevent efficient spread of virus from cell to cell


Viruses and cancer

Vaccines and antisera (Chapter 45)

Immunoglobulins

passive immunization

limitations

sometimes antiviral antibody titers not high enough

contamination with other infectious agents

need to use early after exposure

often this is not possible

some viruses have a limited extracellular phase

herpesviruses, enteroviruses

used against:

Cytomegalovirus

Hepatitis B

Rabies

Respiratory Syncytial Virus

Vaccinia (smallpox)

Varicella zoster


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