Transcript yeast infections

HIV Antiretroviral
Treatment
By: Richard Britt
Dr. Buynak
Spring 2006
Human Immunodeficiency Virus
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HIV is a Retrovirus which means:
It contains a single-stranded RNA genome
 The HIV will incorporate it’s own genome into it’s
host cell and hijack the normal functions of the cell
to replicate itself
 This process will eventually lead to cell destruction
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The target for HIV is the CD-4+ Helper TCells, which are the backbone of the immune
system.
Symptoms
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The Majority of Symptoms of an HIV infection do not
show up until the disease has already begun to damage
the immune system
The incubation time for an HIV infection can be
several weeks to several years
General symptoms include:
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Lack of energy, weight loss, frequent fevers and sweats,
persistent or frequent yeast infections, persistent skin rashes
or flakey skin, short-term memory loss, and mouth, genital,
or anal sores from Herpes infections
Opportunistic Infections
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HIV infection is usually discovered when a
patient is diagnosed with an unusually severe or
persistent infection
Opportunistic infections include:
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Bacterial, Fungal, Parasitic, and Viral Infections
These infections will be more severe because the
person’s immune system will be surpressed by
the HIV disease.
HIV Details
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RNA Genome is 9 kilobases long and contains 9
genes that encode 15 different protiens
Fusion targets of the viral surface envelope
glycoprotiens is the CD4+ receptor and its coreceptor CCR5 on the surface of the Tlymphocyte
Envelope contains the following viral enzymes:
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Reverse Transcriptase, Integrase, RNAse-H
Basic Steps
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HIV fuses with host cell and releases its genome and
enzymes into the cell
RNA genome is transcribed by Reverse Transcriptase
into a single stranded viral DNA
Reverse Transcriptase acts as DNA Polymerase and
transcribes the single stranded DNA into a Double
Stranded Viral DNA
DNA is then transported into the cell nucleus and is
integrated into the host cell DNA by the viral enzyme
integrase.
HIV Lifecycle
More Basic Steps
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Normal functions of the cell resume except now
instead of transcribing RNA for the regular
proteins of the cell it is transcribing viral mRNA
Viral Proteins are produced in one large multiprotein chain from the viral mRNA
Viral Components move toward the cell
membrane and bud off into new immature
virions
HIV Lifecycle
More Basic Steps
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Viral enzyme protease cleaves itself from the
viral protein mass
The Viral Protease then matures the virion by
cutting up the protein mass into the individual
viral enzymes
The virion is a mature and infectious virus
HIV Lifecycle
Mature HIV Virus
Life Cycle Animation
Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
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Zidovudine first drug in this class
approved by the FDA on March
20, 1987
This class of drugs works by
inhibiting the action of the viral
enzyme reverse transcriptase.
This is accomplished by taking the
place of a DNA peptide and
prematurely terminating the
transcription process
NRTIs are phosphorylated three
times after they enter the cell to
become successful inhibitors
Zidovudine
(AZT or azidothymidine)
Nucleotide Reverse Transcriptase
Inhibitors (NtRTIs)
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In the same class of
drugs as NRTIs however
these are not required to
be phosphorylated after
they enter the cell.
Same mechanism of
action as NTRIs
Life Cycle Animation
Tenofovir Disproxil Fumarate
(Viread®)
Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
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Also act as inhibitors of the
viral enzyme reverse
transcriptase however
mechanism of action is
different
This class of drugs works by
non-competitive inhibition
The drug binds to the viral
enzyme at a place other than
the active site and changes
the conformation of the
active site decreasing the
enzyme’s affinity for
nucleoside binding.
Nevirapine (Viramune®)
Life Cycle Animation
Protease Inhibitors
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These work by competitive
inhibition of the viral
enzyme protease
These drugs irreversibly bind
to the active site of protease
preventing it from
completing the maturation of
the virion
Protease inhibitors prevent
immature virions from
becoming mature, infectious
Viruses
Life Cycle Animation
Sequinavir
(Invirase®)
Low
Bioavailability
Ritonvir (Norvir®)
More successful
because it inhibits
Cytochrome P450
3A4 which breaks
down Protease
Inhibitors
Mature HIV Virus
Life Cycle Animation
Fusion Inhibitors
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Newest Class of Drugs
This drug binds to the
glycoprotein gp41 in the viral
envelope inhibiting its fusion
with the CD4+ receptor on
the host cell and thus
preventing the cell’s
infection.
Usually used as a last line
Enfuvirtide (Fuzeon®)
option for most patient
because it is only available as
an injection and its high cost Life Cycle Animation
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More than $25000 per year
Fusion Inhibitors vs. Other Classes
of Drugs
History of Drug Development
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1985 – research on anti-viral medication begins
1987 – First drug Zidovudine produced
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Mid-1990s – Protease Inhibitors and NNRTIs Developed
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First NRTI
Early life extending properties except only temporarily worked as patients
became immune
1995 – first protease inhibitor Sequinavir approved by the FDA
Low Bioavailability led to the development of a second protease inhibitor
Ritonvir
1996 first NNRTI, Nevirapine approved by FDA
March 2003 – First Fusion Inhibitor Enfuvirtide approve by
FDA
Current Research
HIV Vaccine
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Two methods of vaccine research showing
promise
Recombinant Subunit Vaccines
 Live Recombinant Vaccines
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Disadvantages
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Recombinant Subunit Vaccine
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If the recombinant viral envelope proteins that are included
in the vaccine aren’t close enough in structure and
composition to the actual HIV envelope proteins the antigens
that are produced will be ineffective in fighting an actual HIV
infection
Live Recombinant Vaccine
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Can actually cause disease when it is trying to prevent it
Usually occurs when the person is immunocompromised
Sources
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Cervia, Joseph S. and Miriam A. Smith. “Enfuvirtide (T-20): A Novel Human Immunodeficiency Virus Type 1 Fusion Inhibitor.” Clinical Infectious Diseases
2003; 37:1102-1106. NATAP.ORG. 5 April 2005. <http://www.natap.org/2003/oct/100703_1.htm>.
Greenberg, Michael L. and Nick Cammack. “Resistance to enfuvirtide, the first HIV fusion inhibitor.” The Journal of Antimicrobial Chemotherapy. 2004
54(2):333-340. Oxford Journals; British Society for Antimicrobial Chemotherapy: 2004. 5 April 2006.
<http://jac.oxfordjournals.org/cgi/content/full/54/2/333>.
“HIV/AIDS.” eMedicine Consumer Health. WebMD: 2003-2006. 5 April 2006. <http://www.emedicinehealth.com/hivaids/article_em.htm>.
“HIV Fusion Inhibitor.” Panacos. Panacos Pharmaceuticals Inc.: 2006. 5 April 2006. <http://www.panacos.com/product_3.htm>.
“HIV Lifecycle” Roche-HIV.com. F. Hoffmann-La Roche Ltd.: 2006. 5 April 2006. <http://www.rochehiv.com/Newsandfeatures/animations/lifecycle/lifecycle_animation.cfm?link=HIVTreatment#>
“Maenza, Janine, and Charles Flexner. "Combination antiretroviral therapy for HIV infection." American Family Physician 57.n11 (June
1998): 2789(10). InfoTrac OneFile. Thomson Gale. Southern Methodist University. 5 April 2006
<http://find.galegroup.com/itx/infomark.do?&contentSet=IACDocuments&type=retrieve&tabID=T002&prodId=ITOF&docId=A20881343&source=gale&userGroupName=txshracd2548&version=1.0>.
Peiperl, Laurence, Susa Coffey, and Paul Volberding. “HIV InSite Knowledge Base.” Comprehensive on-line textbook of HIV disease from the University
of California San Francisco and San Francisco General Hospital. Regents of the University of California: 2006. 5 April 2006.
<http://hivinsite.ucsf.edu/InSite.jsp?page=KB>.
Phillips, Kenneth D. "Protease inhibitors: a new weapon and a new strategy against HIV." Journal of the Association of Nurses in AIDS Care 7.n5 (Sept-Oct
1996): 57(15). InfoTrac OneFile. Thomson Gale. Southern Methodist University. 5 April 2006
<http://find.galegroup.com/itx/infomark.do?&contentSet=IACDocuments&type=retrieve&tabID=T002&prodId=ITOF&docId=A18944501&source=gale&userGroupName=txshracd2548&version=1.0>.
“Primate Lentivirus Group: HIV-1, HIV-2.” Daniele Focosi. 2001-2005. 5 April 2006. <http://focosi.altervista.org/pathoviruses_HIV.html>
Reisberg, Paul. “HIV Part 1.” Wellesley Chemistry Department: March 8, 1999. 5 April 2006. <http://www.wellesley.edu/Chemistry/Chem101/hiv/HIV1.html>
“Simple Facts Project.” AIDS Treatment Data Network. The Network: 2002. 5 April 2005. <http://www.aegis.com/factshts/network/sf.html>.
Stanic, Anela, and Tulip K. Schneider. "Overview of antiretroviral agents in 2005." Journal of Pharmacy Practice 18.4 (August 2005): 228. InfoTrac
OneFile. Thomson Gale. Southern Methodist University. 07 February 2006
<http://find.galegroup.com/itx/infomark.do?&contentSet=IACDocuments&type=retrieve&tabID=T002&prodId=ITOF&docId=A137362742&source=gale&srcprod=ITOF&userGroupName=txshracd2548&version
=1.0>.
Zapor, Michael J., Cozza, Kelly L., et al. “Antiretrovirals, Part II: Focus on Non-Protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion
Inhibitors).” Psychosomatics; 45:6 (Nov – Dec 2004): 524-535. 5. April 2006 <http://psy.psychiatryonline.org/cgi/reprint/45/6/524>.