M15: Antivirals Flashcards
Human Herpes Viruses (5)
HSV: Herpes Simplex virus
CMV: Cytomegalovirus
EBV: Epstein Barr virus
VZV: Varicella Zoster virus
HHV-8: Human Herpes virus 8
Associated Diseases of Human Herpes Viruses:
HSV: Herpes Simplex virus
CMV: Cytomegalovirus
EBV: Epstein Barr virus
VZV: Varicella Zoster virus
HHV-8: Human Herpes virus 8
Fever blisters, genital herpes, encephalitis
Retinitis, colitis, pneumonia
Mononucleosis, lymphoma
Chickenpox, shingles
Kaposi sarcoma
Associated Diseases of Other Viruses:
HAV: Hepatitis A virus
HBV: Hepatitis B virus
HCV: Hepatitis C virus
HPV: Human Papilloma virus
Influenza A and B
RSV: Respiratory Syncytial virus
HIV
Lassavirus
Enterovirus
Food-borne hepatitis A
Blood-borne hepatitis B
Blood-borne hepatitis C
Warts, cervical/anal cancer
Influenza
Bronchitis, pneumonia
AIDS
Lassa fever
Diarrhea, meningitis
Drugs that Treat Viral Diseases:
1) HSV
2) CMV
3) VZV
4) RSV
5) HBV
6) HCV
7) Influenza A
8) Influenza B
9) Lassavirus
10) Enterovirus
11) HPV
1) *(val)acyclovir, famciclovir, penciclovir, *foscarnet
2) *(val)ganciclovir, *foscarnet, cidofovir
3) *(val)acyclovir, famciclovir
4) *ribavirin, pavilizumab
5) *tenofovir, *emtricitabine, *lamivudine, entecavir, telbivudine, *adefovir
6) *interferon-α, *ribavirin, *telaprevir, *boceprevir, *sofosbuvir, *simeprevir
7) *amantadine, *rimantadine, *oseltamivir, *zanamivir
8) *oseltamivir, *zanamivir
9) *ribavirin
10) pleconaril
11) imiquimod, interferon-α
Immediately lethal viral infections:
Some viral diseases are immediately lethal and these are relatively (common / rare).
However, these outbreaks receive a lot of media attention, often out of proportion to the numbers of humans affected.
These viruses cause intense _ and patients die from _ or _.
Examples: (3)
rare
vascular inflammation
hemorrhage or pulmonary edema
Ebola, Yellow Fever, Hanta viruses
Self limited viral infections:
(Most / Few) viral diseases are self-limited; they cause an illness but then the host develops _ and eradicates the virus through _ and _ response.
a. The immunity can protect the host from re-infection _
Example: _
b. Immunity can be only for a _ duration while decreasing the severity of subsequent infections due to some remaining immunity
Example: _.
c. Some viruses can _ the acquired immunity of the host by changing the antigenic properties of its _
Example: _
Most
immunity
cytotoxic T cells and B cells
life-long
Hepatitis A
short
RSV
overcome
envelope
Influenza
Contained viral infections:
Many viral diseases are _ by the immune system, but are not _. These viruses establish themselves in the host.
a. Chronic persistent infection:
Some viruses cause a chronic persistent infection with _.
• Examples: Hepatitis C can cause _. HIV causes _.
b. Latent infection:
Other viruses remain latent and can _.
Most humans get infected with most of the human _ viruses before adulthood (HSV, VZV, CMV, EBV, HHV-6, HHV-7).
The primary illness is often _ although may not be recognized.
The viruses establish themselves and remain quiescent unless they reactivate spontaneously, due to _ or when the host gets profoundly _.
• Example: _ is caused by primary infection with varicella zoster virus (VZV), dermatomal reactivation can occur later in life in the form of _.
contained
eradicated
ongoing replication
liver cirrhosis
CD4 lymphocyte destruction
replicate during stress or immunosuppressive states
herpes
symptomatic
inflammation
immunosuppressed
Varicella (chickenpox)
zoster (shingles)
Immunization:
Active immunization-Vaccines:
Active immunization with a vaccine elicits an immune response by _ and/or _.
These may protect the host from infection when it encounters the virus for the _ time.
The immunity is often _ as long as the virus does not change its antigenic coat. There are 2 types of vaccines (2)
T-cells (cytotoxic T-cells) and/or neutralizing antibodies by B-cells
first
long-lasting
attenuated
inactivated
Immunization:
Passive immunization- Immunolobulin (Ig):
Passive immunization can protect the host from infection by receiving _ derived from _.
These preparations often contain a minimum titer of _ to be protective for specific viruses.
They neutralize the virus and block its infectivity by prohibiting _.
It (does / does not) elicit any immune response from the host and due to the (long / short) half-life of immunoglobulins (~2 weeks) the protection (is / is not) long lasting.
Recent advances in purification and sterilization made these products much safer than in the past. However, due to shortages and expense they are not widely used.
immunoglobulins
human serum
IgG
viral entry into cells
does not
short
is not
Principles of antiviral therapy:
Virucides:
These are agents that _
Examples (4)
They have a limited use in _ infections, warts (destroying host tissues and virus). Potential use in transmission prevention.
directly inactivate intact viral particles.
detergents, organic solvents, UV light, photodynamic inactivation.
mucocutaneous HSV
Principles of antiviral therapy:
Immunomodulation:
In some instances we can _ the host immune response to better contain or eradicate the virus infection.
a. Inducing host factors with antiviral properties:
Such as _ (cytokine) and _ (cytokine inducer).
They induce degradation of _, inhibit viral _, and enhance _ and _ cells activity.
b. Restoring host immunity:
In specific cases we can restore the host immune response by decreasing _ or treating the cause of the _ state.
Examples: A renal transplant patient may develop post-transplant lymphoproliferative disease (PTLD) from the reactivation of _ due to the immunosuppressed state.
By decreasing his immunosuppressant agents the host can now _ this reactivation but as a consequence may _.
In AIDS patients presenting with _ (HHV-8 or KSHV) we can treat this by starting the patient on antiretrovirals for HIV. The increasing _ count causes regression of the lesions.
stimulate
interferon
imiquimod
viral RNA
protein synthesis
cytotoxic T lymphocytes (CTL) and natural killer (NK)
immunosuppressant medications
immunosuppressed
EBV
contain
reject the kidney transplant
Kaposi sarcoma
CD4
Principles of antiviral therapy:
Antivirals:
These drugs inhibit viral replication at the _ level and they have a restricted spectrum of activity.
They target virus-specific proteins and have (high / low) affinity for host encoded proteins.
For example, acyclovir requires the viral enzyme _ for phosphorylation into its active form. This phosphorylation cannot take place in _ host cells
a. Antiviral drugs act only on _ viruses. Those viruses that are in a _ phase are not using their polymerase enzyme and therefore not susceptible to _. Active HSV replication (genital herpes) can be treated with this antiviral, but the latent HSV in the ganglion cells will not be affected.
b. They are often used too _ to make an impact. By the time patients are _ from the viral infection, billions of host cells have already been infected and several billions of viral particles have been produced.
• Example: _ for influenza is only effective within the first 48 hours of symptoms
c. Rapid development of drug resistance. The high replication rates of viruses require “_” polymerases that work very _ but are not _. Many _ mutations occur and most affect the infectivity. However, some mutations enable the virus to select for medication _. Drug resistane should be suspected when there is lack of clinical and virological response to therapy.
cellular
low
thymidine kinase (TK) uninfected
replicating
quiescent
acyclovir
late
symptomatic
oseltamivir
sloppy fast precise spontaneous resistance
Mechanism of action of antivirals:
Antivirals for Herpes viruses:
a. Nucleoside analogues:
They prevent viral replication by directly inhibiting the _ and by incorporating a faulty _ causing termination of growing RNA or DNA chain.
- Antivirals: (4).
b. Nucleotide analogues:
They prevent viral replication by directly inhibiting the _ and by incorporating a faulty _ causing termination of growing RNA or DNA chain.
- Antiviral: (1)
c. Pyrophosphate analogue:
Inhibits _
- Antiviral: (1)
viral DNA or RNA polymerase
nucleoside
Acyclovir, valacyclovir, ganciclovir, valganciclovir
viral DNA or RNA polymerase
nucleotide
Cidofovir
viral polymerase
Foscarnet
Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Acyclovir:
Mechanism of action:
Acyclovir (ACV) requires intracellular phosphorylation to _ which is the active drug.
The initial phosphorylation requires a viral kinase, called _, subsequent phosphorylations (2nd and 3rd step) by host cellular enzymes.
ACV-TP competitively inhibits _ and acts as a chain terminator due to absence of _.
Spectrum of activity:
_, _, and _ all of which encode the thymidine kinase.
However, there is a descending order of susceptibility (IC50); HSV-1>HSV-2>VZV) so _ or _ require higher doses.
It is important to note that the viral kinase produced by CMV has a very (high / low) affinity to acyclovir.
Extremely high doses of acyclovir would be required to halt the replication of _ thus acyclovir is not considered a drug of choice for infections due to _.
acyclovir-triphosphate (ACV-TP)
thymidine kinase (TK)
viral DNA polymerase
3’ hydroxyl group
HSV-1, HSV-2, and VZV
chickenpox or shingles
low
CMV
CMV
Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Acyclovir:
Clinical use:
a. First episode of orolabial herpes-treatment offers _ symptomatic benefit.
b. Recurrent orolabial herpes (fever blisters): _ benefit in symptoms.
c. First episode of genital herpes: _ benefit in regard to symptoms and healing
d. Recurrent genital herpes: Symptomatic therapy; _ benefit in symptoms. _ therapy (80% reduction of recurrences). Reduces subclinical of viral shedding and transmission (but only by 50%)
e. _ herpes (baby infected from mother)
f. Herpes encephalitis: _ therapy is associated with better outcomes
g. Varicella (chickenpox) in adults with rash
significant
only 1/2 day
significant
only 1 day
Suppressive
Neonatal
prompt
3
adults over 50 years
immunocompromised
Post organ transplantation prophylaxis
