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antiviral therapy
cmbm exam IV
46
Chemistry
Graduate
01/29/2010

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Term
what are targets for antiviral therapy? what needs to be avoided? can latent infections be targeted?
Definition
blocking virus-specific activities including certain enzymes, attachment proteins and steps in the replication cycle that are unique to viruses WITHOUT interfering with host cell function (= toxicity). this can only be directed at actively replicating viruses, not latent infections
Term
what is treated in the case of many acute viral infections?
Definition
the symptoms, and you have to wait for the immune response to do its job of getting rid of the virus
Term
what does successful antiviral therapy require? why is this difficult?
Definition
early initiation of therapy, which is difficult b/c viral replication may precede symptoms -therefore may be more useful as chemoprophylaxis than treatment, (given in anticipation of a flu outbreak or in chronic infections such as HIV, viral hepatitis, herpes)
Term
what are ways that antivirals disrupt viral attachment?
Definition
molecules such as neutralizing antibodies produced in the body can block the binding site of viral attachment proteins, (VAPs). drugs such as peptide or sugar receptor antagonists can act as analogues of the receptor or VAP and are designed to competitively inhibit the binding of the virus.
Term
how is the entry/uncoating step inhibited in antiviral therapy?
Definition
components can be designed to bind at the receptor binding area of capsid proteins & inhibit the dissociation of capsid proteins required for uncoating
Term
why is it had to inhibit viral mRNA synthesis (transcription) with antivirals?
Definition
it is difficult inhibit just viral mRNA synthesis w/out inhibiting host cellular mRNA synthesis. this is b/c DNA viruses often use host enzymes for mRNA synthesis and RNA polymerases encoded by RNA viruses are similar to host cell enzymes
Term
is inhibition of virus genome translation possible? what about blocking post-translational protein modification?
Definition
it is possible to inhibit viral genome translation, but difficult b/c viruses use host protein synthesis machinery. one example of this is oligonucleotides inhibiting translation of viral mRNA. post translational modification of viral proteins is also possible, and a common target for antiviral therapy. examples of this include inhibition of polyprotein cleavage and inhibition of glycoprotein processing, (via inhibition of attachment/fusion)
Term
how is genome replication targeted with antiviral drugs? what is an example? how is the drug's action regulated?
Definition
DNA polymerases (herpes) and reverse transcriptase (HIV) are targeted using nucleoside analogues. these nucleosides are modified in either the base or sugar moiety (some lack a 3' -OH), and therefore it cannot accept a new base to continue. viral polymerases are less accurate than host cell genomes and are thus more likely to incorporate the modified base into the viral genome. acyclovir is an exmple of a guanosine analogue that inhibits the DNA polymerases of herpes. it must be phosphorylated by a viral kinase (thymidine kinase) to be activated, and this is what keeps the drug from being activated in non-affected cells.
Term
how is the assembly and release phase of viral replication targeted by antiviral drugs?
Definition
protease inhibitors can block protease activity required for successful assembly of an infectious viral particle, (inhibitors of the HIV protease prevent maturation of a viral particle into an infectious virion).
Term
what is an example of the assembly and release phase being targeted in terms of the influenza virus?
Definition
neuraminidase is needed in the influenza virus's release of new viral particles, (it cleaves off the sialic acid, which is the hemagglutinin of the virus), anti-influenza drugs zanamivir & oseltamivir inhibit this enzyme which inhibits release of the new viral particles
Term
how is the viral integrity targeted by antiviral drugs?
Definition
enveloped viruses are susceptible to detergents, so nonoxynol-9 (acts like a detergent) can be used against HSV & HIV, (works by disrupting the lipid bilayer)
Term
what is a "productive infection"? non-productive?
Definition
progeny virus is actively being produced and infected cells are permissive for the virus. non-productive is the opposite...
Term
what is a cytopathic effect (CPE)?
Definition
a CPE means there is some pathology going on in the cell; naked viruses always produce this effect and envelope viruses often cause this effect
Term
what does a lytic infection involve? what kinds of viruses produce this effect?
Definition
destruction of the host cell, the most severe cytopathic effect, (CPE). naked virions will produce this effect.
Term
what are syncytia formations?
Definition
a kind of CPE where giant multinucleated cells caused by fusion proteins made by the virus. seen in HIV/RSV
Term
what are inclusion bodies?
Definition
a kind of CPE where regions in the cell where there are a lot of viral components clumped together and you can see them through staining. seen in measles, adenoviruses, herpes
Term
what is cell rounding?
Definition
cells normally have the appearance of cobblestones but sometimes when they are infected, they will pull away from each other and round up. this kind of CPE is seen in adenoviruses and herpesviruses
Term
what does a persistent (chronic) infection involve? how many cells in a population are usually affected by this?
Definition
continual shedding of the virus, and no destruction of the host cell, b/c enveloped viruses use membrane budding. usually with this, only a few cells in the population are infected
Term
can a lytic infection caused by naked viruses be chronic beyond the cellular level?
Definition
yes, the tissue can survive even if individual cells are lysed, eg. adenovirus
Term
what is an abortive infection?
Definition
a kind of nonproductive infection where the host cell cannot support a viral infection and the genome is lost
Term
what is a latent infection? where is this seen? is reactivation possible?
Definition
the virus is dormant within the cell, its genome is maintained - some transcript may be detected, but no new viral particles are being made. this is seen in DNA viruses or retroviruses, (RNA viruses are more labile and therefore cannot be latent). reactivation of a lytic infection is possible, (herpes)
Term
what is immortalization in terms of viral infections of cells?
Definition
immortalization is where the virus sends a signal for the cell to stay in the cell cycle. the viral genome is maintained and some early viral genes are expressed, which can lead to transformation
Term
what is transformation in terms of a virally infected cell?
Definition
transformed cells are permanentyl phenotypically altered by viral provision/activation of growth-stimulating genes, inactivation of growth regulatory genes or prevention of apoptosis
Term
are transformed or immortalized cells considered permissive?
Definition
they are considered semi-permissive
Term
what are some consequences of transformation?
Definition
uncontrolled cell growth, alteration in cell morphology/metabolism (decreased requirement for serum growth factors/alterations in cell surface components/increased metabolic rate) or loss of cell contact inhibition of growth, (cells can pile up on each other)
Term
a productive infection can be either ____ or _____?
Definition
lytic or persistent
Term
what can a persistent infection become?
Definition
chronic
Term
what can a nonproductive infection be?
Definition
abortive, latent or transformint
Term
what can latent or transforming infections become?
Definition
chronic
Term
what can an acute infection be on the host level?
Definition
localized or disseminated
Term
what happens with an acute localized infection on the host level? where are these ofen seen?
Definition
usually a symptomatic productive infection occurs at the site of entry and is subsequently cleared by the immune response, (also many times, acute infections are self-limiting). site of entry is often on mucosal surfaces, so IgA is important for protection from re-infection - but immunity can be short-lived. this kind of infection is often seen with respiratory tract or GI infections. viremia is abesent.
Term
can viral infections be asymptomatic or subclinical? if so, would the individual be considered contagious?
Definition
yes, viruses can cause inapparent infections and still shed virus
Term
what happens when a localized infection disseminates? is this always apparent? is the pt infectious before symptoms become apparent? which viruses is this seen with?
Definition
a productive infection can be asymptomatic at the site of entry and then spread via lymphatics, blood, or neurons and replicate at the secondary site, causing symptoms there, (the pt is thus infectious before symptoms are apparent). secondary viremia also possible. this is seen with enteroviruses, measles, mumps, rubella, varicella, and parovirus B19
Term
what are characteristics of disseminated infections? what Ig is involved?
Definition
virus shedding typically occurs following initial replication, and before symptoms. the incubation period occurs as the virus disseminates and symptoms correlate with replication at the secondary site. IgG is important for immunity here, and is usually life-long
Term
what is a chronic infection? is the inital infection symptomatic? can the pt develop a clinical disease?
Definition
an acute infection can process to a chronic (persistent) infection where symptoms may not be visible, but viral shedding is occuring (both on the cellular level - host cell not destroyed and tissue level - only a few cells are destroyed). the initial infection may/may not be sympomtatic and the pt can develop a clinical disease over time. (chronic hepatitis B/C, HIV)
Term
what is a latent infection? can the virus be detected during this time? what is reactivation characterized by? is there a difference in clearance between primary and secondary infections?
Definition
a kind of chronic infection where the virus is not shed until reactivation. the virus cannot be detected during latency. reactivation may/may not be symptomatic and secondary infections are cleared more rapidly than primary infections. (herpes/papillomavirus are examples)
Term
what is the host objective in infections?
Definition
clear the pathogen, prevent dissemination, prevent future infections
Term
what is the pathogen objective in infections?
Definition
avoid the host immune system long enough to be transmitted to a new host
Term
why do many viruses have to be highly efficient in transmission?
Definition
many have humans as their only host
Term
what is the "hit & run" strategy? what level of virulence/immunity do they induce?
Definition
replicate & find a new host before being cleared by the immune response. this is seen often with respiratory viruses and immunity is usually not long lasting. these viruses may not be very virulent as well
Term
what is a common viral strategy for viruses that are persistent/chronic?
Definition
transmission over time, latency/reactivation allows a way of finding new hosts over an extended period of time and the ability to hide from an immune response. the carrier state does this as well, but is more at risk of an immune response
Term
other than latency, how can viruses avoid an immune response?
Definition
antigenic variation, incorporation of host membrane glycoproteins in the viral envelope, and modulation of immune response
Term
are symptoms always directly caused by a virus?
Definition
no, often symptoms are related to the immune response
Term
what viral factors influence the characteristics of disease in terms of site of entry, inoculum size and tissue tropism?
Definition
route of transmission determines site of entry, inoculum size will influence severity of infection, and tissue tropism determines site of pathology (determined by specificity of viral attachment proteins)
Term
what are common viral virulence factors?
Definition
mechanisms to enhance viral replication while inhibiting host cell protein synthesis, mechanisms to evade the host immune system, ability to produce a cytopathic effect (CPE), cause cell lysis, or induce apoptosis
Term
what are host factors influencing characteristics of disease?
Definition
immune status, (compromised versus non-compromised immune system OR prior immunity), general nutritional health of pt, age (influences efficiency of the immune response), and genetic background
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