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Targets for Anti-viral therapy
1. viral attachment to cell and fusion (fusion inhibitors)
2. protein translation in infected cells (interferon)
3. protein processing (specific protease inhibitors)
4. DNA synthetic enzymes (reverse transcriptase inhibitors,
DNA polymerase inhibitors)
5. DNA integrase
6. Immune system (effective vaccines, restore immune
surveillance)
Acyclovir

FDA approved in 1982
 structural analog of deoxyguanosine
 mechanism of selective toxicity
• phosphorylated by viral thymidine kinase (TK)
• preferential incorporation by viral DNA polymerase
• causes chain termination

~20% oral bioavailability (valacyclovir is 3-5X better)
 penetrates CSF
 effective in treating


primary Herpes infections (genital, encephalitis, neonatal)
chronic Herpes (does not cure but can reduce recurrence)
Acyclovir
mechan
ism of action
Acyclovir is activated and concentrates in HSV infected cells
Treatment of HSV Recurrent infections
• chronic therapy with acyclovir, valacyclovir, famciclovir
• therapeutic vaccines: using HSV-2 surface protein gD2
-has shown 30% reduced recurrence
• immune response modifiers: imiquimod/resiquimod
-act by inducing cytokines (interferon alpha,
interleukins) that stimulate macrophage and antigen
presenting cells
-clinical trials were initially promising but have now
been halted due to lack of sufficient therapeutic effect
Resistance to acyclovir
 mutations

alter affinity for drug or just completely inactivate the
gene
 viral

in viral TK gene
DNA polymerase mutations
reduce recognition of phosphorylated drug as
substrate for DNA synthesis
Virus prevents glycolipid antigen presentation
to natural killer T cells by down regulating
CD1d expression
antigenic
glycolipids
endogenous
phospholipids
LTP=lipid transfer
protein
Ganciclovir
 for
CMV, varicella zoster (chicken pox/shingles)
 similar to acyclovir
 6-9% oral bioavailability
 penetrates CSF
 more active than acyclovir against CMV
 toxicity: bone marrow suppression, CNS
(headaches, convulsion, psychosis)

some toxic effects seen in about 40% of pts
Foscarnet






binds to pyrophosphate site of viral polymerase (also
RTase)
100 fold greater selective inhibitor or viral versus
human polymerase
poor oral bioavailability
nephrotoxicity is high (~50%) but reversible
hypocalcemia and CNS toxicity is also significant (25%
pts)
useful in acyclovir/ganciclovir resistant HSV or CMV
Interferons
Interferons are glycoproteins that come in 3 varieties:
a (made in leukocytes) induced by viral infection,
IL1, IL2, TNF
b (made in fibroblasts)
g (made in T cells) activated T cells produce g interferon
to modulate the immune response
Cytokine signaling pathway
Multiple Pathways of Interferon Action
Clinical use of Interferon

alpha interferon FDA approved:

genital warts (papillomavirus)




note: resiquimod has also been shown to be effective
hepatitis B and C
Kaposi’s sarcoma (HSV VIII)
Toxicity


fever, fatigue, marrow suppression, depression, acute
influenza like symptoms
about 10-20% discontinue therapy due to toxicity
Hepatitis C

Chronic hepatitis C virus (HCV) infection affects 2.7
million people in the United States.
 Cirrhosis of the liver resulting from chronic HCV
infection is the leading reason for liver transplantation
in the U.S.
 Drug treatments such as interferon and ribavirin are
not very effective
 HCV protease inhibitors are a promising new class of
antivirals for this disease
• BILN 2061 (Boehringer) looked good but appears to have
cardiovascular toxicity and is on hold
• VX-950 (Vertex Pharmaceuticals) is now in phase II trials and looks
promising
Recent report (Oct. 2003) of a novel protease inhibitor that
blocks protease required for Hepatitis C Virus function
Telaprevir (VX-950) with peg-IFN
looks promising in clinical trials
Anti-influenza virus drugs

Amantadine, Rimantadine




only active against influenza A
blocks the influenza M2 ion channel on endosomes and prevents
passage of H+ ions required for acidification and viral uncoating
mild CNS effects
Zanamivir, Oseltamivir


active against both influenza A and B
inhibits influenza viral neuraminidase. Neuraminidase must cleave
terminal sialic acid residues on receptors recognized by viral
hemagglutinin. Without this cleavage, virus remains trapped on
infected cells --no release of infectious particles
Targets for treatment of HIV (anti-retroviral drugs
Zidovudine (AZT)
RTase inhibitor
 from


bench to bedside in about 1 yr.
Oct 85--in vitro activity
Feb 86--clinical trial halted




<1% death rate on AZT 12% death rate on placebo
Oct 86--available in Seattle
Jan 87--FDA approved
only drug specifically for HIV until lamivudine
developed in 1995
Zidovudine
 mechanism

selective reverse transcriptase inhibitor
Zidovudine (AZT)
(thymidine analog)
Mechanism of selective toxicity of AZT
DNA
synthesis
AZT concentration (uM)
Zidovudine

mechanism


pharmacokinetics:

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bone marrow depression (anemia, leukopenia)
headache, nausea, myopathy, anorexia, fatigue
therapeutic effects:



orally active, penetrates CSF
toxicity:


selective reverse transcriptase inhibitor
increase CD4+ T cells partially restoring immune system
reverses AIDS dementia
resistance: major problem

RTase mutations
Lamivudine (3TC)
 similar
to zidovudine
 resistance develops quickly: selects for
met184val mutation in RTase
 lamivudine + zidovudine combination
dramatically slows resistance development
NNRTIs
(non-nucleoside
reverse transcriptase
inhibitors)
HIV-1 protease stereo-structure with Sequinavir
SAQUINAVIR
INDINAVIR
RITONAVIR
NELFINAVIR
AMPRENAVIR
LOPINAVIR
Drug regimen
does not attack
non-replicating
virus
CCR5 and CXCR4 antagonists

Vicriviroc (Schering): Oct,
2005 discontinued Phase II
trial due to therapeutic failure
in some pts
 Aplaviroc (GlaxoSmithKline):
Oct, 2005 Phase III trials
halted due to hepatotoxicity
 Pfizer still has a compound in
trials
gp120
gp41
virus
Effects of Fuzeon (enfuvirtide, T-20) treatment on
viral load (FDA approved in March, 2003)
Initial Treatment:
Preferred Components
NNRTI Option
NRTI Options
Efavirenz*
OR
PI Options
Atazanavir + ritonavir
Fosamprenavir + ritonavir (BID)
Lopinavir/ritonavir (BID)
+
Tenofovir +
emtricitabine**
Zidovudine +
lamivudine**
*Avoid in pregnant women and women with significant
pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
9/07
Initial Treatment:
Alternative Components
NNRTI Option
Nevirapine*
OR
NRTI Options
Abacavir +
lamivudine
PI Options
Atazanavir**
Fosamprenavir
Fosamprenavir + ritonavir (1x/day)
Lopinavir/ritonavir (1x/day)
Didanosine +
(emtricitabine or
lamivudine)
*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400
cells/mm3
**Atazanavir must be boosted with ritonavir if used in combination with tenofovir
9/07
How does HIV escape the host
defense mechanisms?
 APOBEC3G
is a host cytosine deaminase that
mutates the viral DNA and would destroy it
 HIV expresses a protein, vif, that binds C3G
and targets it to the proteasome for degradation
•APOBEC3G is a cellular cytidine deaminase that inactivates HIV
by causing strand breaks or hypermutation
•Viral vif protein targets APOBEC3G for degradation by the
proteasomal pathway
Therapeutic Implications?
drugs that could interfere with APOBEC3G/vif interaction
would block production of infectious virus
 gene therapy with vif resistant APOBEC3G?
 patients with polymorphisms in APOBEC3G may be more or
less resistant to HIV infection?
 high mutation rate due to cytidine deaminase activity of
APOBEC3G may increase rate of drug resistance
development
 probably explains why HIV is so species specific


vif may interact with the primate APOBEC3G selectively
Number of people living with HIV