Anti Virals Flashcards
how do anti-virals work
they suppress the rate of replication of a virus so the host immune system can fight the infection
what is the structure of the herpes virus
spherical iscoahedron, double stranded linear DNA, enveloped, more than 35 proteins
what are the features of the herpes virus
encodes any enzymes, establish latent infections, lifelong persistence, significant cause of death in immunocompromised hosts, some can cause cancer
what are the three subfamilies of the herpes virus
alpha, beta, gamma
what distinguishes the herpes virus subfamilies
their genetic makeup
what strains of herpes are alpha subfamily
herpres simplex virus types 1 and 2, varicella-zoster virus
what strains of herpes are beta subfamily
cytomegalovirus, human herpesvirus 6 and 7
what strains of herpes are gamma subfamily
epstein-barr virus, human herpesvirus 8
what does HSV-1 cause
oropharyngeal sores in children
what does HSV-2 cause
herpes genitalia in young adults
what are the virulence factors of HSV-1 and HSV-2
gC bonds complement C3b (innate immune system)
gE is an Fc receptor for IgG (adaptive immune system)
how are HSV strains spread
by contact; the virus is shed in saliva, tears, genital and other secretions
what is the replication cycle of HSV-2
- host cell membrane fuses with viral envelope so nucleocapsid can enter the cytoplasm
- viral capsid is uncaoted and viral DNA of the genome enters the cell’s nucleus
- new viral DNA is synthesised by the nucleus
- mRNAs transported on cytoplasmic ribosomes into capsid and spike proteins
- capsid proteins enter the nucleus and combine with viral genomes to form new nucleocapsids
- viruses bud through the nuclear membrane but do not acquire their final envelope and spikes until reaching a Golgi cimpartment in the cytoplasm; exocytosis releases the new virons
what is aciclovir
structural analogue of guanosine that inhibits viral DNA synthesis
what formulations does aciclovir come in
topical, oral, IV
what viruses can aciclovir treat
HSV1 and 2, varicellar-zoster virus
what is the aciclovir mechanism of action
prodrug phosphorylated to aciclovir tri-phosphate (carried out by a viral thymidine kinase) with subsequent phosphorylation from host kinases
it is a chain terminator that gets incorporated into replicating viral DNA strand and blocking further replication; its incorporated by viral DNA polymerase
treatment for HSV-2
aciclovir 400mg tds for 7-10 days
valaciclovir 1000mg bd for 7-10 days
famciclovir 250mg tds for 7-10 days
what is valaciclovir
L-valyl ester drodrug of aciclovir
only available orally but has high oral bioavailability due to ester
what are the adverse effects of valaciclovir
headache, nausea, weakness, dizziness, confusion
what is famiciclovir
cyclic guanine analogue, converted to penciclovir in the liver and intestines
only available orally
what formulation is penciclovir used in
topical only, due to poor bioavailability
what are some adverse effects of famiciclovir
headache, GI
what is the structure of the varicellar-zoster virus
double stranded DNA, enveloped virus, long and short genome fragments, only one antigenic serotype
what age group does VZV infect
4-10 year olds
how does VZV gain entry to the target site
through the respiratory tract and then spreads to the lymphoid system, it incubates for 14 days then arrives at the skin
where does VZV remain latent
in the cerebral or posterior root ganglia
can be dormant for decades
what happens when VZV reactivates in ganglion
tracks down the sensory nerve to the area of the skin supplied by the nerve, producing a vericella form rash in the distribution of a dermatome
what does the varicellar virus cause
chickenpox
what is the incubation period of varicellar
14-21 days
how does varicellar present
fever and widespread vesicular rash
what is herpes zoster
shingles
what age group are commonly affected by herpes zoster
50+ years
how does herpes zoster occur
latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment
characteristic eruption of vesicles in the dermatome which is often accompanied by intensive pain lasting for months
how is varicellar virus managed
self-limiting disease
aciclovir can accelerate resolution time
what drugs can be used for the treatment of herpes zoster
aciclovir, valaciclovir and famiciclovir
what are the replication stages for HIV infection
- adsorption - virus attaches to host cell by specific binding of spikes to cell receptors
- penetration - the virus is engulfed into a vesicle by endocytosis
- uncoating - envelope of the virus is removed and RNA is freed into the cytoplasm
- synthesis - replication and protein production - cell synthesises RNA molecules, capsomers and spikes of viruses
- assembly - viral spike proteins are inserted into the cell ,e,brane for the viral envelope; nucleocapsid is formed from RNA and capsomers
- release - enveloped viruses bud off, carrying away an envelope with the spikes, ready to infect another cell
what is the structure of HIV
icosahedral, enveloped retrovirus, ssRNA virus
contains two copies f RNA, enzymes and envelope proteins
what is a retrovirus
transcribes RNA to DNA
what enzymes does the HIV virus contain
reverse transcriptase, integrase, protease
what envelope proteins does the HIV virus contain
gp120, gp41 (protein binding)
how does HIV replicate
HIV gp120 protein mainly binds to CD4 receptors, but other receptors are involved in infection (called co-receptors)
CD4 defines the cell type that HIV will infect
what are the main co-receptors in HIV replication
CCR-5
CXCR4
which receptor will HIV use
very few HIV strains can use both receptors
most people have HIV that uses either CCR-5 or CXCR4
steps of HIV replication -
what enzyme copies viral DNA within the cell
reverse transcriptase
what is the site of action of AZT
reverse transcriptase (synthesis of viral DNA in the cell)
how does the HIV infiltrate the cell
via co-receptors, which internalise the contents
steps of HIV replication -
what is the role of integrase functions
to incorporate DNA into host cell genome (integrated provirus)
they are not used in unintegrated proviruses as DNA just circularises
they circularise viral DNA and form a preincorporation complex which moves into the nucleus; integrated protein inserts viral DNA into cell nucleus DNA - this is a permanent change in the cell
what is the site of action for integrase inhibitors
the DNA incorporation into host cells by integrase enzymes
why is HIV called a retroavirus
it uses reverse transcriptase which converts RNA back to DNA
what happens in HIV replication after host cells are activated
viral DNA is transcribed, yielding mRNA and viral genome RNA
what happens to viral RNA during HIV replication
they are translated, yielding viral enzymes (including protease) and structural proteins
what happens to viral membrane proteins during HIV replication
they are transported to host cell membrane
what happens during the final stage of HIV replication
final viral assembly and budding take place
what is the role of protease in HIV replication
it ‘chops’ long polypeptide chain that are inactive to allow them to be active as smaller proteins (chains of viral genetic info)
what drugs target HIV replication
NRTIs - nucleoside/nucleotide reverse transcriptase inhibitors
NNRTIs - non-nucleoside reverse transcriptase inhibitors
PIs - protease inhibitors
fusion inhibitors
integrase inhibitors
CCRS antagonists (entry inhibitors)
what is Fuzeon
fusion inhibitor
blocks entry of HIV into cells (CD4 or T cells)
mimics components of Gp41 and displaces them, preventing normal fusion
it causes change in cell shape
what is the mechanism of HIV fusion
- HIV approaches host CD4+ T-cell (its viral membrane contains trimeric glycoprotein spikes with each spike containing gp41 and gp120 subunits)
- fusion begins with the binding of gp120 to CD4 and chemokine receptors on the cell membrane
- binding induces conformational change in gp120, exposing gp41
- fusion is mediated by gp41, which contains two heptad repeat domains, HR1 and HR2
- ‘zipping’ - gp41 is exposed, the hydrophobic terminus of gp41 embeds itself into the cell membrane. the HR2 domain coils into grooves exposed on trimeric HR1 domain of gp41. this destabalises both cell and viral membranes punching a hole into both membranes which allows the HIV capsid to pass through the cell membrane
what shape if HR1 used in HIV fusion
spiral/coil
what shape is HR2 used in HIV fusion
disordered, floppy chain
what is the relationship between HR1 and HR2 in HIV fusion
HR2 coils down HR1 which strains and breaks membranes; allowing fusion of HIV with the T-cell
what is the mechanism of Fuzeon
peptide mimic of HR2 region of gp41, so it binds to the HR1 region
zipping cannot take place so the infection is blocked
it competitively binds to the HR1 before HR2 can ‘zip’, preventing membrane stress
what action do CCR5 entry inhibitors have
they block the attachment of HIV to the CCR5 receptor, halting HIV replication
CXCR4 receptors will be unaffected, so replication can continue
how do integrase inhibitors work
targets integrase enzymes that incorporate viral DNA into host cells
breaks DNA by breaking bond between sugar and phosphate which requires metal ions; drug competes for metal ions
how do nucleoside/nucleotide RT inhibitors work
based on the structure of nucleotides/nucleosides and lack a hydroxyl group
NTRIs act as chain terminators or inhibitors at the substrate binding site of reverse transcriptase
how do non-nucleoside RT inhibitors work
inhibit viral DNA replication by binding at the allosteric non-binding site of RT, causing a confrontational change of the active site
how do protease inhibitors work
proteases process GAG and POL polyproteins into mature HIV components. PI drugs contain a hydroxyethylene bond instead of a peptide bond, which makes PIs non-scissile substrate analogues for HIV protease
drugs mimic shape to bond and prevent breaking/cleaving of bonds so are competitive inhibitors
what does HAART stand for
highky active anti-retroviral therapy
what is the common combination of HAART drugs used
3 anti-retrovirals from at least two different classes (2NRTIs and 1NNRTI, PIs or II)
reduces resistance
what can be a side effect of HAART
liver disease due to toxicity
what is a nucleocapsid
capsid and nucleic acid of a virus
what is a naked virus
without an envelope, only the nucleocapsid
how are DNA viruses release from host cells
budded off the nucleus
how are RNA viruses released from host cells
they multiply and are then released from the cytoplasm
what are the two main modes of penetration used by viruses
endocytosis and fusion
what form of penetration do naked viruses use
endocytosis
what method of penetration do encapsulated viruses use
fusion
what is viral pathogenesis
the process where a viral infection leads to disease
disease is abnormal and of no advantage to the virus
what are the outcomes of acute viral infection
no residue effects, recovery with residue effects like neurological issues, death, chronic infection
what are the outcomes of chronic infection
silent subclinical infection for life, long period before disease, reactivation to cause acute disease, chronic disease with relapses and exacerbations, cancers
what factors determine viral pathogenesis
cellular pathogenesis, entry into host, course of infection, cell/tissue tropism, cell/tissue damage. host immune response, virus clearance or persistance
what are some methods of transmission for viruses
respiratory transmission, faecal-oral transmission, blood-bourne transmission, sexual transmission, animal or insect vectors
what are the sites of viral entry
skin, conjunctiva or mucous membranes, respiratory tract, gastrointestinal tract
what is primary replication
where the virus replicates after gaining entry into the host
this determines whether infection is localised or spread
what is systemic spread
spreading of a virus via bloodstream or CNS
what is secondary replication
infection taking place at susceptible organs/tissues following systemic spread
what is cell tropism
viral affinity for specific body tissues
what determines cell tropism
cell receptors for virus, cell transcription factors that recognise viral promoters and enhancer sequences, ability of cell to support virus replication, physical barriers, temp/pH/O2, digestive enzymes may inactivate some viruses
what are the effects of picornaviruses
cause cell lysis and death when they replicate, leading to fever and increased mucous secretion
like rhinovirus or poliovirus
what are the primary events in the innate immune response
induction of type 1 interferons
activation of NK cells
what happens during induction of type 1 interferons
double stranded RNA of the virus induces the expression of the interferons by the infected cell
the bound interferons will activate the JAK/STAT pathway responsible for the synthesis of several genes (one encodes 2-5A synthetase that activates ribonuclease)
what role do interferons and natural killer cells have
IFN-alpha and IFN-beta binding induces a specific protein kinase called RNA-dependent protein kinase
the binding to NK cells induces lytic activity which is effective in killing virally infected cells and enhanced by IL-12
what is the function of antibodies
if produced to the viral receptor, can block infection and prevent binding to host cells
some can cause lysis of enveloped virions
some agglutinate viral particles and function as opsonising agent
what are the two main components of cell-mediated antiviral defence
CD8+T cells
CD4+T cells
how do viruses respond to host-immune responses
they encode proteins that interfere at various levels
some evade IFN-alpha/beta action, some inhibit antigen presentation, some evade complement-mediated destruction, some cause immunosuppression-direct viral infection of lymphocytes or macrophages, some constantly change their antigens
