V I R U S in computer…??
A V I R U S is a program or programming code thatreplicatesAttaches itself to a file enabling it to spread from onecomputer to another, leaving infections as it travels
Viruses
Obligate intracellular parasitesConsist of a core genome in a protein shell and some are surrounded by a lipoproteinLack a cell wall and cell membraneDo not carry out metabolic processesReplication depends on the host cell machineryFor replication it has to attach a cell
Steps for Viral Replication
Binding of the virus to the host cellPenetration into the host cellUn-coating of the virionReverse transcriptionEntry of DNA into the nucleusTranscription of provirus into mRNAmRNA translation by host ribosomesAssembly & buddingRelease of new virions
Classification
1. Anti-Herpes virusIdoxuridineAcyclovir ValacyclovirFamciclovirGanciclovir *Foscarnet *
* Not marketed in India
Anti-Retrovirus
a) Nucleoside reverse transcriptase inhibitors (NRTIs)Zidovudine (AZT)DidanosineZalcitabineStavudineLamivudineAbacavir
Herpes viruses 2 type:-
Herpes simplex type I and II
Type I cause disease of mouth, face & skin
Type II affects genitals, rectum and skin
Vidarabine- 1st agent to be developed
Too toxic
Idoxuridine, Acyclovir, Famciclovir, Ganciclovir,
Foscarnet
Mechanism of Action Acyclovir
An acyclic guanosine derivative
Phosphorylated by viral thymidine kinase
Di-and tri-phosphorylated by host cellular kinases
Inhibits viral DNA synthesis by:
1) competing with dGTP for viral DNA polymerase
2) chain termination
Genital Herpes simplex
By type II HSV
Topical /oral / parenteral
Primary disease - Early5% ointment locally6 times a day for 10 days
Late cases – 400mg TDS oral 10d
H.Simplex keratitis
Better for deep stromal infection
Eye ointment
5 times a day till 3 days after healing
Chikenpox
Immunodeficient and neonate
15mg/kg/day for 7 days is DOC
In susceptible contacts –
Oral Acyclovir 400 mg 4 times a day for 7 days
Side Effects: Acyclovir
Stinging and burning sensation - topical
Nausea, diarrhea - oral
Headache
Tremors
Skin rash and delirium
Dose dependent decrease in GFR
Valacyclovir
L-valyl ester of acyclovir
Converted to acyclovir when ingested
M.O.A.: same as acyclovir
Uses:
1) recurrent genital herpes
2) herpes zoster infections
Side Effects: nausea, diarrhea, and headache
Famciclovir
Prodrug of penciclovir
A guanosine analogue
M.O.A.: same as acyclovir
Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B
Side Effects: nausea, diarrhea, and headache
Idoxuridine
Thymidine analog
Competes with thymidine & gets incorporated in DNA
Formation of faulty DNA
Synthesis of wrong viral proteins
Unwanted effect
Bone marrow depression
Trifluridine (5-iodo-2-deoxyuridine)
Trifluridine- fluorinated pyrimidine
inhibits viral DNA synthesis same as acyclovir
incorporates into viral and cellular DNA
Uses: HSV-1 and HSV-2 (topically)
Vidarabine
An adenosine analog
Inhibits viral DNA polymerase
Incorporated into viral and cellular DNA
Metabolized to hypoxanthine arabinoside
Side Effects: GI intolerance, myelosuppression
Ganciclovir
An acyclic guanosine analog
Requires triphosphorylation for activation
M.O.A.: same as acyclovir
Uses: CMV*, HSV, VZV,and EBV
Side Effect: myelosuppression
FoscarnetAn inorganic pyrophosphate
Inhibits viral DNA polymerase, RNA polymerase, and
HIV reverse transcriptase
Does not have to be phosphorylated
Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV
Resistance due to mutations in DNA polymerase
Side Effects: hypo- or hypercalcemia ,phosphotemia
Fomivirsen
An oligonucleotide
M.O.A.: binds to mRNA and inhibits protein synthesis
and viral replication
Uses: CMV retinitis
Side effects: Iritis and increased IOP
Human immunodeficiency virus
Virus classificationGroup: Group VI (ss RNA-RT)Family: Retroviridae
Genus: Lentivirus
SpeciesHuman immunodeficiency virus 1Human immunodeficiency virus 2
Comparison of HIV species
Species Virulence Transmittability Prevalence Purported origin
HIV-1 High High Global Common Chimpanzee
HIV-2 Lower Low West Africa Sooty Mangabey
STRUCTURE AND GENOME OF HIV
Roughly spherical
About 120 nm
ss-RNA
Nucleocapsid- p 24
Matrix – p 17
Envelope protein – gp 120,
gp41
Enzymes – RT, Integrase, Proteases
HIV tropism
CD4+ cells
1. T helper cells
2. Macrophage/Monocytes
3. Microglial cells
4. Langerhan cells
Co receptors
1. CCR5 – β chemokines (MCP1, RANTES)
2. CXCR4 – α chemokines (SDF 1)
Classes of Antiretroviral drugs
Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Protease inhibitors (PIs)
Integrase inhibitors
Entry inhibitors ( fusion inhibitors)
Maturation inhibitors
Broad spectrum inhibitors
Zidovudine (AZT)
Didanosine (ddI)
Lamivudine (3TC)
Stavudine (d4T)
Zalcitabine (ddC)
Abacavir (ABC)
Emtricitabine (FTC)
# Apricitabine, Stampidine, Elvucitabine , Racivir, Amdoxovir.
NtRTIs - Tenofovir
Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)
Clinical Uses Zidovudine
Available in IV and oral formulations
Activity against HIV-1 and HIV-2
Mainly used for treatment of HIV, decreases rate
of progression and prolongs survival
Prevents mother to newborn transmission of HIV
Other NRTIs
Didanosine- synthetic deoxy-adenosine analog; causes pancreatitis*
Lamivudine- cytosine analog
Zalcitabine- cytosine analog; causes peripheral neuropathy*
Stavudine- thymidine analog; causes peripheral neuropathy*
Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz NevirapineDelavirdine
Diarylpyrimidines (Etravirine, Rilpivirine)Loviride
Mechanism of ActionNNRTIs
Bind to site on viral reverse transcriptase
Results in blockade of RNA dependent DNA
polymerase activity
Does not compete with nucleoside triphosphates
Does not require phosphorylation
Substrates and inhibitors of CYP3A4
b) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Nevirapine - prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery
Delavirdine - teratogenic
Efavirenz- teratogenic
Protease Inhibitors
The protease enzyme cleaves precursor molecules to produce mature, infectious virions
These agents inhibit protease and prevent the spread of infection
These agents cause a syndrome of altered body fat distribution, insulin resistance and hyper-lipidemia
Saquinavir
A synthetic peptide-like substrate analog
Inhibits HIV-1 protease
Prevents cleavage of viral polyproteins
Nelfinavir and Amprenavir
M.O.A.: Specific inhibitors of the HIV-1 protease
Less cross-resistance with Amprenavir
Side Effects: diarrhea and flatulence
Amprenavir can cause Stevens-Johnson syndrome
Contraindications: inhibitor/substrate for CPY3A4
Entry Inhibitors
gp41 - Enfuvirtide
CCR5 - Maraviroc, Vicriviroc†, PRO 140†
CD4 - Ibalizumab †
† Undergoing clinical trials, not FDA approved
Maturation inhibitors
Bevirimata drug designed to halt the development of immature HIV particles after they have emerged from human cells .
Treatment should be aggressive
Suppress viral load to undetectable lebel - < 50 copies/ml
With 3 ARDs is optimal
Choice is based on efficacy, durability, tolerability and cost
3 drugs in regimen should belong to at least 2 different groups
NRTI + NRTI + NNRTINRTI + NRTI + PI
3 NRTI regimen is employed when a NNRTI/PI cant be used
PI sparing regimen more convenient with less pill burden, simple dose schedule
3 class regimen for advances cases
HAARTCombination of three or more antiretroviral drugs
The preferred initial regimens are:
efavirenz + zidovudine + lamivudine
efavirenz + tenofovir + emtricitabine
lopinavir boosted with ritonavir + zidovudine + lamivudine
lopinavir boosted with ritonavir + tenofovir + emtricitabine
HIV Post exposure Prophylaxis[PEP]
28-day HIV drug regimen
The minimum that should be used is dual NRTIs for 28
days, with triple therapy (dual NRTIs plus a boosted PI)
being offered where there is a risk of resistance .
Most effective the sooner the drugs are administered.
Mother-to-child transmission of HIV-1
The pregnant woman should start
Zidovudine (AZT) from 28 weeks or as soon as possible thereafter
single-dose Nevirapine (NVP) when entering labour
AZT+3TC for one week following delivery.
*Meanwhile, whether the mother was on the above or standard
ART, the child should be given single dose Nevirapine immediately
after delivery and daily Zidovudine until one week old .
Which of the following is not a protease inhibitor
SaquinavirRitonavirAbacavirNelfinavir
Abacavir – a NRTI
InterferonsInterferon AlfaEndogenous proteins
Induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA
Bind to membrane receptors on cell surface
May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release
Amantadine and Rimantadine
Cyclic amines
It blocks the viral membrane protein, M2 which functions as ion channel
used in the prevention and treatment of Influenza A
Any other use of Amantadine..???
Parkinsonism
Treatment Tamiflu (oseltamivir)
Relenza (zanamivir)
April 27, 2009, the Food and Drug Administration (FDA)issued Emergency Use Authorizationsto make available Relenza and Tamiflu