Lecture 20: antiviral drugs Flashcards
(57 cards)
What are some characteristics of viruses?
Obligate intracellular parasites
No cell wall or plasma membrane
No metabolism (tough to target)
Few drugs block reproduction selectively
Pharmacology focused on late symptoms
Few virus groups can be effectively treated with drugs
Virus classification
(+)ssRNA - HIV, Hep A and C (can give direct protein synthesis)
dsDNA - Hep B, Herpes
(-) ssRNA -Influenza
See figure
What are the cytopathic effects of viruses?
Host cell metabolism hijacked
Viral-induced suppression of host homeostasis
Viral proteins induce lysis or apoptosis
Viral proteins trigger host immune response
Inflammatory reaction kills host
All above involve lytic cycle (generation of new virus)
Viruses can become latent, host cell survives
No overt immune response
What cells does Herpes simplex virus target?
Neurons (neurotropic)
What type of genome does HSV have?
Complex dsDNA
What symptoms does HSV cause?
HSV-1: cold sores
HSV-2: genital herpes
Chicken pox (varicella zoster - VZV), shingles, cytomegalovirus
How is HSV transmitted?
Close contact
HSV life cycle
Lytic cycle: in epithelial cells (80 genes in cascade)
Viral progeny spread to sensory neurons
Virus is retrogradedly transported to the cell body of the neuron
Latent infection: circular episomal DNA (not incorporated into genome)
No immune signature, no cytotoxic effect
Stress-related reactivation
Anterograde transport (similar to how neurotransmitter is transported)
See figure
HSV replication
Viral DNA enters nucleus and circularizes
Immediate early genes (IEG) are transcripts by the host RNA polymerase (2-4 hours post infection).
This transcription uses host transcription factors and VP16, a viral activator protein, which binds host cell factor that activates OCT1 (host transcription factor)
IEG proteins trigger early genes
E proteins control viral DNA replication
DNA replication initiates late genes, which are responsible for viral structure and assembly
See figure
How does acyclovir work?
HSV treatment
The viral thymidine kinase converts acyclovir to acyclo-GMP.
Host enzymes convert acyclo-GMP to acyclo-GTP.
Acyclo-GTP is incorporated into the growing DNA, and causes chain termination.
It is an inhibitor of the viral DNA polymerase.
See figure
Where is cytomegalovirus (CMV) a problem?
In immuno-compromised patients (organ transplantation)
What are the complications of CMV?
Liver failure
Colitis
Retinitis (inflammation of retina, can cause blindness)
What type of virus is HIV?
Lentivirus (HIV-1 and HIV-2)
Retrovirus family (+) ssRNA virus
Fast replication cycle and multiple infection
What enzymes is most responsible for drug resistance in HIV?
Reverse transcriptase
Enzyme is error prone = drug resistance
What does HIV cause?
AIDS
90% of people progress to AIDS within 10-15 years
How is HIV transmitted?
Blood/fluid
What cells does HIV invade?
T helper cells (CD4+)
Macrophages, dendritic cells
What receptors does HIV target?
CD4 receptors and chemokine co-receptors (CCR5, CCR4)
What types of immunity are lost in HIV infection?
Cell-mediated immunity
Loss of CD4+ cells
Development of aids - CD4+ count and HIV RNA copies
See figure
Initially, during primary infection, the CD4+ cell count is high. The virus starts to replicate rapidly, which causes the CD4+ cell count to drop
During clinical latency, the virus replicates slowly, and the CD4+ cell count drops
Eventually, there are very low CD4+ cells in the blood, and the virus takes over
This predisposes the host to opportunistic diseases etc.
Epidemiology of HIV
High in Africa
Origin of HIV
Started in Africa
Person from Haiti travelled to Africa and likely contracted HIV from a sex worker
Haitian then returned to haiti and transmitted virus by donating blood
People visiting Haiti for vacation contract the virus
See figure
Treatment options for HIV
No cure
Post-exposure prophylaxis
Highly active antiretroviral therapy (HAART) - 3 drugs belonging to at least 2 classes
Newer integrase and entry inhibitors can be added
Aggressive treatment in children
Points of intervention in HIV replication cycle
See figure
Fusion inhibitors
CCR5 antagonists
Reverse transcriptase inhibitors
Integrase inhibitors
Protease inhibitors
