Lecture 29: Antiviral Medications

Question 1

What are viruses?

Answer 1

viruses are obligate intracellular parasites - rely on host biosynthetic machinery to reproduce

when not inside an infected cell, viruses exist as independent particles (virions)

simplest viruses encode 4 proteins; most encode 100-200 proteins (compare to humans ~20,000)

Question 2

What are virions?

Answer 2

double or single stranded DNA or RNA

a protein coat (capsid)

some also possess a lipid envelope derived from the host cell which, like the capsid, may contain antigenic glycoproteins

~1/100th the size of the average bacterium

Question 3

What is a viral range?

Answer 3

viral range is the group of cell types (or species) that a virus can infect

Question 4

What is a bacteriophage?

Answer 4

virus that infects only bacteria is called a bacteriophage

Question 5

What are animal viruses or plant viruses?

Answer 5

viruses that infect animals or plants are referred as animal viruses or plant viruses

most animal viruses to do not cross phyla, and some only infect closely related species (i.e. humans and primates for poliovirus)

Question 6

What is virus shape?

Answer 6

viruses can be classified based on the shape of their capsid

helical, icosahedral, complex

Question 7

What is pathogenicity?

Answer 7

ability of viruses to cause disease is pathogenicity

Question 8

What is virulence?

Answer 8

degree of pathogenicity

Question 9

What is latency in viruses?

Answer 9

some viruses can remain dormant in organisms - called latency

i.e. varicella zoster (chicken pox, shingles)

Question 10

What are carriers?

Answer 10

people chronically infected are called carriers and serve as reservoirs of infectious virus

Question 11

What is the viral replication cycle?

Answer 11

“life” cycle of viral replication: absorption, penetration, replication, and release

surface of viruses have proteins that bind to receptor protein on host cell; interaction determines the host range of a virus and begins the infection process (i.e. HIV and CD4)

viral DNA or RNA crosses the plasma membrane to the cytoplasm or nucleus

once inside, viral DNA or RNA interacts with host machinery for translating DNA or RNA into viral protein

newly synthesized virion particles are released to continue infection cycle

Question 12

What is the central dogma of biology?

Answer 12

eukaryotes and prokaryotes make protein from an mRNA template DNA –> mRNA –> protein (one direction)

DNA can either be transcribed (into mRNA) or replicated (make more DNA)

DNA replication and transcription happen in the nucleus

protein translation (mRNA –> protein) happens in the cytoplasm (in ribosomes)

Question 13

What are RNA and DNA viruses?

Answer 13

there are RNA viruses and DNA viruses

can be single stranded or double stranded

Question 14

What are DNA viruses?

Answer 14

most DNA viruses enter the host cell nucleus, where the viral DNA is often integrated into the host genome and transcribed into mRNA by host DNA-dependent RNA polymerase; mRNA is translated into virus-specific proteins (DNA –> RNA –> protein)

poxviruses are an exception; they carry their own DNA-dependent RNA polymerase and replicate in the host cell cytoplasm

viral genome replication requires DNA-dependent DNA polymerase from the host or virus

Question 15

What are RNA viruses?

Answer 15

double stranded RNA viruses require RNA-dependent RNA polymerases, so virus must make itself (RNA –> mRNA)

the viral RNA-dependent RNA polymerase acts both as a transcriptase to transcribe mRNA and a replicase to replicate the viral genome

most RNA viruses complete their replication in the host cell cytoplasm, but some, such as influenza, are transcribed in the host cell nucleus

Question 16

What are retroviruses?

Answer 16

retroviruses have an RNA genome that directs the formation of a DNA molecule (RNA –> DNA –> mRNA –> protein)

the viral enzyme reverse transcriptase copies viral RNA into DNA (RNA-dependent DNA polymerase)

the resulting viral DNA is integrated into the host DNA (then transcribed into mRNA and translated into protein by host enzymes)

most retroviruses do not immediately kill their host cells, rather infected host cells can continue to replicate producing daughter cells with integrated proviral DNA

Question 17

What is vaccination?

Answer 17

vaccination is a cheap and effective way of preventing infections by viruses

vaccines are available to prevent other thirteen viral infections in humans, and more are used to prevent viral infections of animals

vaccines can consist of live-attenuated or killed viruses, or viral proteins or mRNA (antigens)

Question 18

What are anti-virals?

Answer 18

anti-viral drugs can exert actions at several stages of viral replication including viral entry, nucleic acid synthesis, protein synthesis, viral packaging, and virion release

combination therapy can result in greater clinical effectiveness against viral infections and can also prevent or delay the emergence of resistance

anti-viral drugs are virustatic - only active against replicating viruses and do not affect latent virus

Question 19

What are anti-herpes drugs?

Answer 19

acyclovir is a nucleoside analog (fake DNA binding block) which viruses incorporate into their genomes during replication

acyclovir lacks a hydroxyl group important for forming the backbone of the DNA molecule (DNA chain termination)

the life cycle of the virus is halted because the newly synthesized DNA is inactive

Question 20

What is the mechanism of acyclovir?

Answer 20

acyclovir must be phosphorylated to acyclovor-triphosphate to be incorporated into viral DNA as a terminal substrate

the first phosphate group is added by the herpes simplex virus thymidine kinase, which has an affinity for acyclovir that is about 200 times that of the mammalian enzyme (specificity)

Question 21

What can acyclovir resistance in the herpes simplex virus result from?

Answer 21

impaired production of viral thymidine kinase

altered thymidine kinase substrate specificity (e.g., phosphorylation of thymidine but not acyclovir)

altered viral DNA polymerase

Question 22

What is HIV?

Answer 22

human immunodeficiency virus (HIV) is a lentivirus, a family of retroviruses that lead to chronic persistent infection with gradual onset of clinical symptoms

HIV infects human immune cells (CD4+ T cells); when CD4+ T cells decline below a critical level, cell mediated immunity is lost and the body becomes susceptible to opportunistic infections (AIDS)

replication is constant following infection; in the absence of treatment there generally is no true period of viral latency following infection

Question 23

What is the treatment for HIV?

Answer 23

anti-viral HIV drugs target viral infection at multiple levels (fusion, transcription, integration into host genome, and virion release)

current HIV treatment usually involves 3 or more antiretroviral drugs

highly active antiretroviral therapy (HAART) involving drug combinations can slow or reverse the increases in viral RNA load that normally accompany progression of disease

Question 24

What are entry inhibitor anti-virals for HIV?

Answer 24

HIV infection begins with attachment of HIV envelope proteins called gp120 to CD4 and CCR5 receptors on surfaces of T cells

entry inhibitors interfere with binding, fusion, and entry of an HIV virion into a human cell

i.e. Maraviroc is a CCR5 receptor antagonist (interferes with HIV binding to T cell)

Question 25

What are nucleoside reverse transcriptase inhibitors (NRTI) anti-virals for HIV?

Answer 25

HIV reverse transcriptase enzyme synthesizes DNA from HIV RNA using nucleosides in the host T-cell (RNA dependent DNA polymerase)

NRTI are small molecule drugs that are similar to the host cell nucleosides, and are incorporated into new HIV DNA chain as if they were endogenous nucleosides

because NRTIs lack a 3’hydroxyl group on the ribose ring, attachment of the next nucleoside is impossible - chain termination

mammalian RNA and DNA polymerases are sufficiently distinct to permit a selective inhibition of viral reverse transcriptase

Question 26

What are integrase strand transfer inhibitors (INSTs) anti-virals for HIV?

Answer 26

integrase is a viral enzyme that inserts viral genome into the DNA of a host cell

integrase inhibitors block the action of integrase to inhibit HIV proliferation

i.e. Raltegravir

Question 27

What protease inhibitor anti-virals for HIV?

Answer 27

assembly of infectious HIV virions is dependent on aspartate proteases; this viral enzyme cleaves precursor proteins to form the final structural proteins of the mature virion core

HIV protease inhibitors are designer dugs based on molecular characterization of the active site of the viral enzyme

usually used in combination with reverse transcriptase inhibitors

Question 28

What is the anti-influenza drug amantadine?

Answer 28

inhibit an early step in replication (viral uncoating) of the influenza A virus

M2 protein functions as a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase

amantadine block proton (H+) transfer through M2, thus blocking acidification and the initiation of viral transcription

Question 29

What are the limitations of the anti-influenza drug amantadine?

Answer 29

amantadine is prophylactive against influenza A (not B) virus infection and can reduce duration of symptoms if given within 48 hours after contact

however, many resistant influenza A virus mutants (i.e., H3N2)

vaccination against influenza is a more cost-effective means of reducing disease burden

seasonal prophylaxis using anti-virals is an alternative in high-risk patients, if the influenza vaccine cannot be administered or may be ineffective (i.e. in immunocompromised patients)

Question 30

What is the anti-influenza drug zanamivir?

Answer 30

inhibitor of neuraminidases produced by influenza A and B

these enzymes cleave sialic acid residues from viral proteins that enables virus to be released from the host cell

by interfering with these actions, neuraminidase inhibitors impede viral spread