IV. VIRUSES
J. CONTROL OF VIRUSES (ANTIVIRAL AGENTS)
The overall purpose of this Learning Object is:
1) to learn how our antiviral control agents affect viruses; and
2) to introduce a number of chemical agents used to control certain viral infections.
Viruses are infectious agents with both living and nonliving characteristics.
1. Living characteristics of viruses
a. They reproduce at a fantastic rate, but only in living host cells.
b. They can mutate.
2. Nonliving characteristics of viruses
a. They are acellular, that is, they contain no cytoplasm or cellular organelles.
b. They carry out no metabolism on their own and must replicate using the host cell's metabolic machinery. In other words, viruses don't grow and divide. Instead, new viral components are synthesized and assembled within the infected host cell.
c. The vast majority of viruses possess either DNA or RNA but not both.
Control of Viruses (Antiviral Agents)
Since viruses lack the structures and metabolic processes that are altered by common antibiotics, antibiotics are virtually useless in treating viral infections.
To date, only a few chemotherapeutic agents have been found to be somewhat effective against just a few limited viruses.
Most antiviral agents, however, work by inhibiting viral DNA synthesis. These drugs chemically resemble normal DNA nucleosides (def), molecules containing deoxyribose and either adenine, guanine, cytosine, or thymine. Viral enzymes then add phosphate groups to these nucleoside analogs to form DNA nucleotide (def) analogs. The DNA nucleotide analogs are then inserted into the growing viral DNA strand in place of a normal nucleotide. Once inserted, however, new nucleotides can't attach and DNA synthesis is stopped. They are selectively toxic because viral polymerases are more prone to incorporate nucleotide analogs into their nucleic acid than are host cell polymerases.
Antivirals used for viruses other than HIV include:
1. amantadine (Symmetrel): used prophylactically (def)) against influenza A in high-risk individuals. Prevents influenza A viruses from the uncoating step necessary for viral replication.
2. rimantidine (Flumadine): used for treatment and prophylaxis of influenza A. Prevents influenza A viruses from the uncoating step necessary for viral replication.
3. zanamivir (Relenza): used to limit the duration of influenza A and B infections. Inhibitor of the influenza virus surface enzyme called neuraminidase that is needed for release of newly formed influenza viruses from the infected cell.
4. oseltamivir (Tamiflu): used limit the duration of influenza infections. Inhibitor of the influenza virus surface enzyme called neuraminidase that is needed for release of newly formed influenza viruses from the infected cell.
5. acyclovir (Zovirax): used against herpes simplex viruses (HSV) (def)) to treat genital herpes, mucocutaneous (def)) herpes in the immunosuppressed, HSV encephalitis (def)), neonatal (def)) herpes, and to reduce the rate of recurrences of genital herpes. It is also used against varicella zoster viruses (VZV) (def)) to treat shingles (def)). Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
6. trifluridine (Viroptic): used to treat eye infection (keratitis and conjunctivitis) caused by HSV. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
7. famciclovir (Famvir): used to treat HSV and VZV infections. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
8. valacyclovir (Valtrex): used to treat HSV and VZV infections. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
9. penciclovir (Denavir): used in treating HSV infections. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
10. ganciclovir (Cytovene; Vitrasert): used in treating severe cytomegalovirus (CMV) (def)) infections such as retinitis (def).
11. valganciclovir (Valcyte): used in treating severe CMV infections such as retinitis). Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
12. foscarnet (Foscavir): used in treating severe CMV (def)) infections such as retinitis (def)). Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
13. cidofovir (Vistide): used in treating CMV retinitis. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
14. fomivirsen (Vitravene): used in treating CMV retinitis. Fomivirsen inhibits cytomegalovirus (CMV) replication through an antisense RNA (microRNA or miRNA (def)) mechanism. The nucleotide sequence of fomivirsen is complementary to a sequence in mRNA transcripts (see Fig. 14) that encodes several proteins responsible for regulation of viral gene expression that are essential for production of infectious CMV. Binding of fomivirsen to the target mRNA results in inhibition of protein synthesis, subsequently inhibiting virus replication.
15. ribavirin (Copegus; Rebetol; Virazole): used in treating severe acute respiratory syndrome (SARS). In combination with other drugs it is used to treat hepatitis C virus (HCV). Chemically resembles a normal RNA nucleoside . Once inserted into the growing RNA chain it inhibits further viral RNA replication.
16. telaprevir (Incivek) for the treatment of chronic hepatitis C (hepatitis C virus or HCV genotype 1). A protease inhibitor (def) that binds to the active site of an HCV-encoded protease and prevent it from cleaving the long polyprotein from polycistronic HCV genes into proteins essential to the structure and function of HCV.
17. boceprevir (Victrelis) for the treatment of chronic hepatitis C (hepatitis C virus or HCV genotype 1) infection. Used in combination with peginterferon alfa and ribavirin. A protease inhibitor (def) that binds to the active site of an HCV-encoded protease and prevent it from cleaving the long polyprotein from polycistronic HCV genes into proteins essential to the structure and function of HCV.
18. lamivudine (Epivir-HBV): used in treating chronic hepatitis B. Chemically resembles a normal DNA nucleoside . Once inserted into the growing DNA chain it inhibits further viral DNA replication.
19. adefovir dipivoxil (Hepsera): used in treating hepatitis B.
Most antiviral agents, however, work by inhibiting viral DNA synthesis. These drugs chemically resemble normal DNA nucleosides (def), molecules containing deoxyribose and either adenine, guanine, cytosine, or thymine. Viral enzymes then add phosphate groups to these nucleoside analogs to form DNA nucleotide (def) analogs. The DNA nucleotide analogs are then inserted into the growing viral DNA strand in place of a normal nucleotide. Once inserted, however, new nucleotides can't attach and DNA synthesis is stopped. They are selectively toxic because viral polymerases are more prone to incorporate nucleotide analogs into their nucleic acid than are host cell polymerases.
Current anti-HIV drugs include the following (classified by their action):
1. HIV nucleoside-analog reverse transcriptase inhibitors (def))
In order to replicate, HIV uses the enzyme reverse transcriptase to make a DNA copy of its RNA genome. A complementary copy of this DNA is then made to produce a double-stranded DNA intermediate which is able to insert into host cell chromosomes to form a provirus (def)).
Most reverse transcriptase inhibitors are nucleoside analogs. A nucleoside is part of the building block of DNA, consisting of a nitrogenous base bound to the sugar deoxyribose but no phosphate group. A nucleoside analog chemically resembles a normal nucleoside.
Once phosphate groups are added by either viral or host cell enzymes, the drugs now chemically resemble normal DNA nucleotides (def) , the building block molecules for DNA synthesis. The nucleotide analog binds to the active site of the reverse transcriptase which, in turn, inserts it into the growing DNA strand in place of a normal nucleotide. Once inserted, however, new DNA nucleotides are unable to attach to the drug and DNA synthesis is stopped. This results in an incomplete provirus. For example, zidovudine ( ZDV, azidothymidine, AZT, Retrovir) resembles the deoxyribonucleotide containing the base thymine. Once zidovudine is inserted into the growing DNA strand being transcribed from the viral RNA by reverse transcriptase, no further nucleotides can be attached (see zidovudine, step-1, zidovudine, step-2 , and zidovudine, step-3).
Examples of nucleoside reverse transcriptase inhibitors include:
a. zidovudine (AZT; ZDV; Retrovir)
b. didanosine (ddI; dideoxyinosine; Videx)
c. stavudine (d4T; Zerit)
d. lamivudine (3TC; Epivir)
e. abacavir (ABC; Ziagen)
f. emtricitabine (FTC; Emtriva, Coviracil)
2. Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
A NtRTI inhibitor ia a nucleotide analog. A nucleotide is the building block of DNA, consisting of a nitrogenous base bound to the sugar deoxyribose, and a phosphate group. A nucleotide analog chemically resembles a normal nucleotide. The nucleotide analog binds to the active site of the reverse transcriptase which, in turn, inserts it into the growing DNA strand in place of a normal nucleotide. Once inserted, however, new DNA nucleotides are unable to attach to the drug and DNA synthesis is stopped. This results in an incomplete provirus. An example of nucleoside reverse transcriptase inhibitor is tenofovir (TDF;Viread).
3. HIV Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (def)
These drugs do not resemble regular DNA building blocks. They bind to an allosteric site that regulates reverse transcriptase activity rather than to the enzyme's active site itself as do the above nucleoside analogues (see Fig. 1). This also prevents HIV provirus formation.
a. nevirapine (NVP; Viramune)
b. delavirdine (DLV;Rescriptor)
c. efavirenz (EFV; Sustiva)
d. rilpivirine (Edurant)
e. etravirine (ETR, TMC125; Intelence)
3. HIV Protease Inhibitors (PIs)
In order for maturation of HIV to occur, a HIV enzyme termed a protease (def) has to cleave a long HIV-encoded gag-pol polyprotein (def) to produce reverse transcriptase and integrase (coded by the HIV pol gene) and gag polyprotein (coded by the HIV gag gene). The HIV protease then cleaves the gag polyprotein into capsid protein p17, matrix protein p24, and nucleocapsid protein p7, as well as proteins p6, p2, and p1 whose functions are not yet fully understood (see HIV protease step-1, step-2, and step-3). Proteases also cleave the env-polyprotein (coded by the HIV env gene) into the envelope glycprroteins gp120 and gp41 (see Fig. 3). Protease inhibitors (def) are drugs that bind to the active site of this HIV-encoded protease and prevent it from cleaving the long gag-pol polyprotein and the gag polyprotein into essential proteins essential to the structure of HIV (see Fig. 3E) and to RNA packaging within its nucleocapsid (see HIV protease, step-3). As a result, viral maturation does not occur and noninfectious viral particles are produced.
Protease inhibitors include:
a. saquinavir (SQV; Inverase)
b. ritonavir (RTV; Norvir)
c. idinavir (IDV; Crixivan)
d. nelfinavir (NFV; Viracept)
e. amprenavir (APV; Agenerase)
f. atazanavir (ATV; Reyataz)
g. fosamprenavir (FPV; Lexiva)
h. ritonavir (RTV; Norvir)
i. darunavir (DRV; TMC114; Prezista)
j. tipranavir (TPV; Aptivus)
4. Entry Inhibitors (EIs)
EIs are agents interfering with the entry of HIV-1 into cells. During the adsorption and penetration stages of the life cycle of HIV, a portion or domain of the HIV surface glycoprotein gp120 binds to a CD4 molecule on the host cell. This induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor. This brings about another conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 that enables the viral envelope to fuse with the host cell membrane. EIs interfere with various stages of this process.
a. Agents that block the binding of gp120 to host chemokine receptor 5 (CCR5).
After the gp120 on the envelope of HIV binds to a CD4 molecule on the host cell, it must then also bind to a co-receptor - a chemokine receptor. CCR5-tropic strains of HIV bind to the chemokine receptor CCR5 (see Fig. 2). (An estimated 50%-60% of people having previously received HIV medication have circulating CCR5-tropic HIV.)
maraviroc (MVC; Selzentry; Celsentri) is a chemokine receptor binding blocker.
b. Agents that block the fusion of the viral envelope with the cytoplasmic membrane of the host cell.
enfuvirtide (ENF; T-20; Fuzeon) binds a gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of the viral envelope with the cellular cytoplasmic membrane.
5. Integrase Inhibitors
Integrase inhibitors disable HIV integrase, the enzyme that inserts the HIV double-stranded DNA intermediate into host cell DNA. Prevents production of a provirus.
raltegravir (Isentress)
6. Fixed-dose combinations
Tablets containing two or more anti-HIV medications.
1. abacivir + lamivudine (Epzicom)
2. abacivir + lamivudine + zidovudine (Trizivir)
3. efavirenz + emtricitabine + tenofovir DF (Atripla)
4. emtricitabine + tenofovir DF (Truvada)
5. lamivudine + zidovudine (Combivir)
Certain cytokines (def) have now been produced by recombinant DNA technology (see Unit-4) and several are showing some success for viral infections. These include:
1. recombinant interferon alfa-2a (Roferon-A): a cytokine used to treat Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia.
2. peginterferon alfa-2a (Pegasys) : used to treat hepatitis C (HCV).
3. recombinant interferon-alpha 2b (Intron A): a cytokine produced by recombinant DNA technology and used to treat Hepatitis B; malignant melanoma, Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, warts, and Hepatitis C.
4. peginterferon alfa-2b (PEG-Intron; PEG-Intron Redipen): used to treat hepatitis C (HCV).
5. recombinant Interferon alfa-2b plus the antiviral drug ribavirin (Rebetron): used to treat hepatitis C (HCV).
6. recombinant interferon-alpha n3 (Alferon N): used to treat warts.
7. recombinant iInterferon alfacon-1 (Infergen) : used to treat hepatitis C (HCV).
None of the current antiviral agents kill and eliminate the viruses, they simply inhibit their replication and decrease the severity of the disease. In the case of some drugs, resistant virus strains are starting to emerge.
Since there are no antiviral drugs for the vast majority of viral infections and the few drugs that are available are only partially effective against limited types of viruses, to control viruses, we must rely on the body's immune responses. As will be seen in detail in Units 4 and 5, the immune responses include innate immunity as well as adaptive immunity (antibody production and cell-mediated immunity). Adaptive immunity can be either naturally acquired or, in some cases, artificially acquired.
For a more detailed description of any specific antimicrobial agent, see the website of RxList - The Internet Drug Index.
Student-Authored Descriptions of Viral Infections
Astroviruses by Michele Stedding
Coxsackievirus by Mandy Hughes
Coxsackievirus by Salyna Riggs
Cytomegalovirus (CMV) by Cindi Chou
Ebola by Christine Sprinkle
Ebola by Dianne Bettick
Ebola by LaTanya Gary
Epstein-Barr Virus (EBV) by Erica Rome
Hantavirus by Jennifer Robinson
Hepatitis A (HAV) by Anastasiya Lyudkevich
Hepatitis B (HBV) by Karen Neff
Hepatitis C (HCV) by Rosemary Bewley
Hepatitis C (HCV) by Corinne Borel
Herpes Simplex types 1 and 2 (HSV1 &HSV2) by Katrina Armstrong
Herpes Simplex types 1 and 2 (HSV1 & HSV2) by Cindy Dubs
Herpes Simplex type 2 ( HSV2) by Lauren Bentley
Human Immunodeficiency Virus (HIV) by Steven Merrill
Human Papilloma Viruses (HPV) by Megan Johnson
Human Papilloma Virus (HPV) by Laura Moy
Influenza by Kenneth Agboifo
Measles (Rubeola) by Peggy Engel
Measles (Rubeola) by Sumara Choudhry
Measles (Rubeola) by Yashu Karki
Mumps by Trudy Ann Hinds
Noroviruses by Kristina Garner
Poliomyelitis by Deborah Malin
Rabies by Pamela Russillo
Rabies by Lauren Mekalian
Rhinoviruses (colds) by Nina Mezu
Rift Valley Fever by LaWanda Morgan
Respiratory Syncytial Virus (RSV) by Ben Kaufman
Respiratory Syncytial Virus (RSV) by Christen Strickler
Rotaviruses by Chrissy Blake
Rotaviruses by Shana Lucas
Varicella (chickenpox) by Rosemary Brunet
Varicella (chickenpox) by Violeta Genova
Viral Meningitis by Denise Grandea
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Updated: June, 2011
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