Transcript HIV treatments

PHM142 Fall 2014
Instructor: Dr. Jeffrey Henderson
42 million worldwide living with HIV , of which the majority are in poor
countries with little to none therapeutic resources. RNA retroviral infection
initiates incorporation of DNA to host chromosome after activity of viral
reverse transcriptase.
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Two parts of the
envelop; external surface
proteins composed of
gp120 and gp41 which
anchor the viron to the
cell surface
Matrix protein; p17
located on the inner
membrane ensures the
full inclusion of viral
proteins
Capsid made up of p24
(gag protein) which
contains two (+) non
coding ssRNA strands,
reverse transcriptase,
integrase, and protease
HIVs genetic structure
http://hivbook.com/tag/structure-of-hiv-1/
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Antiviral agents commonly used in the therapy of immunodeficiency
virus (HIV), as well as Hepatitis B, and cancer
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HIV encoded RNA dependent DNA polymerase called reverse
transcriptase- inhibitors for this enzyme
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Zidovudine was the first drug approved which after phosphorylation
competes with dTTP for a site on the transcript of the DNA
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Amdoxovir: phase II
clinical trials and is
designed to be more
soluble and bioavailable
It is rapidly absorbed
and deaminated to
generate a second
structure which is then
phosphorylated
Reverset: competes with
dCTP
Mitsuya H, Yarchoan R, Broder S (1990). "Molecular targets for AIDS therapy". Science 249
(4976): 1533–44.
Slide 9:Chan DC, Kim PS (1998). "HIV entry and its inhibition". Cell 93 (5): 681–4.
Slide 9: Wyatt R, Sodroski J; Sodroski (1998). "The HIV-1 envelope glycoproteins: fusogens,
antigens, and immunogens". Science 280 (5371): 1884–8.
The virus has a RNA genome
 Once inside the cell, the virus uses its
viral reverse transcriptase to make a
DNA complement strand from the RNA
 DNA dependent DNA polymerase then
makes opposite DNA strand and then
this viral double stranded DNA
molecule is incorporated into the cell’s
genome
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Mitsuya H, Weinhold K, Furman P, St Clair M, Li, Lars, Lehrman S, Gallo R, Bolognesi
D, Barry D, Broder S (1985). "3'-Azido-3'-deoxythymidine (BW A509U): an antiviral
agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic
virus type III/lymphadenopathy-associated virus in vitro". Proc Natl Acad Sci USA 82
(20): 7096–100.
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Nucleoside analogues used in HIV treatments are designed to
be preferentially used by reverse transcriptase
Once inside the body’s cells, the analog has three phosphate
groups added to the 5’ OH to become activated
Once bound to the growing DNA strand they prevent further
elongation of the strand, since they lack a 3’ OH, and cause
premature termination of strand elongation
Premature product is non-functional
Thymidine
Azidothymidine (AZT)
Retroviral Reverse
Transcriptase is
the cause of most
mutations.
 No exonucleolytic
proofreading
 Error rate goes as
high as 1/1700
nucleic acids
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Nucleosides
selects and
destroy the virus.
 This ultimately
selects for
resistance with
the rise of
resistant strains.
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Insertion of amino acids at position 69
and 70 in the finger subdomain causes
resistance to Nucleoside Analogues
 Insertion associated with changes in
flanking amino acids at position 215
 T215F/Y mutation makes ATP binding
to RT more effective increasing excision
of zidovudine (AZT) in vivo
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M184V increases susceptibility to other
drugs (tenofovir, adefovir, zidovudine)
and is a result of treatment with
lamivudine and abacavir
 K65R mutation causes resistance to
most nucleoside analogues with the
exception of zidovudine
 Both mutations together causes an
increased susceptibility to zidovudine.
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Zidovudine (or
azidothymidine, AZT), was
the first antiretroviral drug
approved for HIV treatment
First breakthrough in AIDS
treatment, reducing virus
replication significantly
AZT took 25 months from the first indications of its effectiveness against
HIV to approval, the shortest time in recent history
Phase II studies were modified mid-trial
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6 months: 16 deaths in placebo, 1 in AZT
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initially approved for small subset - Pneumocycstis carinii, 60%
first trials were in patients with advanced AIDS, median survival rate was
increased by a year
after approval for this group of patients, trials began to test effectiveness
in early stages of HIV infection
Mitsuya, H., Yarchoan, R., and Broder, S. “AIDS Therapies.”
Scientific American 259.4 (1988):110-119.
Wright, Karen. “AIDS Therapy: First Tentative Signs of Therapeutic
Promise.” Nature 323.6086 (1986):283.
originally unclear whether resistance to AZT could develop,
or the long-term toxic effects
short-term toxic effects were known
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toxic to bone marrow, patients often developed anemia,
and low numbers of WBC and platelets
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this could limit the amount of drug administered
initial dosing was once every 4 hours, all day and night
HIV did eventually develop resistance to AZT alone
currently used as part of highly active antiretroviral therapy
- HAART
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can reduce viral load to below the limit of detection
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in countries where patients have access to current HIV
therapies, lifespans are significantly increased
chronic illness vs death sentence
Hurtley, Stella. “Take HAART.” Science 303.5664 (2004):1585
1. Boyer, P., Sarafianos, S., Arnold, E., & Hughes, S. (n.d.). Nucleoside Analog Resistance Caused by Insertions in
the Fingers of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involves ATP-Mediated Excision. U.S.
National Library of Medicine National Institutes of Health. Retrieved October 6, 2014, from
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136461/
2. JD, R., K, B., & TA, K. (n.d.). Result Filters. U.S. National Library of Medicine. Retrieved October 6, 2014, from
http://www.ncbi.nlm.nih.gov/pubmed/2460925
3. Hurtley, Stella. “Take HAART.” Science 303.5664 (2004):1585
4. Laurence, B and Chabner, B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, eleventh
edition. 2010. pp. 1309-1315
5. Mitsuya, H., Yarchoan, R., and Broder, S. “AIDS Therapies.” Scientific American 259.4 (1988):110-119.
6. Mitsuya H, Yarchoan R, Broder S (1990). "Molecular targets for AIDS therapy". Science 249 (4976): 1533–44.
Slide 9:Chan DC, Kim PS (1998). "HIV entry and its inhibition". Cell 93 (5): 681–4.
Slide 9: Wyatt R, Sodroski J; Sodroski (1998). "The HIV-1 envelope glycoproteins: fusogens, antigens, and
immunogens". Science 280 (5371): 1884–8.
7. Moyle, G. (n.d.). How the HIV-1 Reverse Transcriptase Mutations K65R, M184V and K65R + M184V Produce
Resistance to NRTIs. TheBodyPRO.com. Retrieved October 6, 2014, from
http://www.thebodypro.com/content/art38455.html
8. V,Vivet-Boudou, J. Didierjean, C. Isel and R. Marquet. Nucleoside and nucleotide inhibitors of HIV-1 replication.
Cell. Mol. Life Sci. 63 (2006) 163-186.
9. Wright, Karen. “AIDS Therapy: First Tentative Signs of Therapeutic Promise.” Nature 323.6086 (1986):283.
•Antiviral agents used in HIV, Hepatitis B and cancer. HIV encoded RNA
dependent DNA polymerase called reverse transcriptase.
•The virus has a RNA genome
•Once inside the cell, the virus uses its viral reverse transcriptase to make a
DNA complement strand from the RNA
•DNA dependent DNA polymerase then makes opposite DNA strand and then
this viral double stranded DNA molecule is incorporated into the cell’s genome
•Once inside the body’s cells, the analog has three phosphate groups added to
the 5’ OH to become activated
•Once bound to the growing DNA strand they prevent further elongation of the
strand, since they lack a 3’ OH, and cause premature termination of strand
elongation
•Premature product is non-functional
•Retroviral Reverse Transcriptase is the cause of most mutations. No
exonucleolytic proofreading
•short-term toxic effects were known
•toxic to bone marrow, patients often developed anemia, and low numbers of
WBC and platelets
•HIV did eventually develop resistance to AZT alone - currently used as part of
highly active antiretroviral therapy – HAART -can reduce viral load to below the
limit of detection