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PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson.

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1 PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

2 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.

3  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

4  Antiviral agents commonly used in the therapy of immunodeficiency virus (HIV), as well as Hepatitis B, and cancer  HIV encoded RNA dependent DNA polymerase called reverse transcriptase- inhibitors for this enzyme  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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6  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

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8 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.

9  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 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.

10  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 Azidothymidine (AZT)Thymidine

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13  Retroviral Reverse Transcriptase is the cause of most mutations.  No exonucleolytic proofreading  Error rate goes as high as 1/1700 nucleic acids

14  Nucleosides selects and destroy the virus.  This ultimately selects for resistance with the rise of resistant strains.

15  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

16  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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19 Zidovudine (or azidothymidine, AZT), was the first antiretroviral drug approved for HIV treatment First breakthrough in AIDS treatment, reducing virus replication significantly

20 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 6 months: 16 deaths in placebo, 1 in AZT 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 Wright, Karen. “AIDS Therapy: First Tentative Signs of Therapeutic Promise.” Nature (1986):283. Mitsuya, H., Yarchoan, R., and Broder, S. “AIDS Therapies.” Scientific American (1988):

21 originally unclear whether resistance to AZT could develop, or the long-term toxic effects short-term toxic effects were known toxic to bone marrow, patients often developed anemia, and low numbers of WBC and platelets this could limit the amount of drug administered initial dosing was once every 4 hours, all day and night

22 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 in countries where patients have access to current HIV therapies, lifespans are significantly increased chronic illness vs death sentence Hurtley, Stella. “Take HAART.” Science (2004):1585

23 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 2. JD, R., K, B., & TA, K. (n.d.). Result Filters. U.S. National Library of Medicine. Retrieved October 6, 2014, from Hurtley, Stella. “Take HAART.” Science (2004): Laurence, B and Chabner, B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, eleventh edition pp Mitsuya, H., Yarchoan, R., and Broder, S. “AIDS Therapies.” Scientific American (1988): 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 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) Wright, Karen. “AIDS Therapy: First Tentative Signs of Therapeutic Promise.” Nature (1986):283.

24 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


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