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HIV Treatment using Nucleoside Analo gs

HIV Treatment using Nucleoside Analo gs. PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson. HIV Infection.

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HIV Treatment using Nucleoside Analo gs

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  1. HIV Treatment using Nucleoside Analogs PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

  2. HIV Infection • 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. HIV Virion • 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/

  4. Overview of Nucleoside Analogues • 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

  5. Combination Drug Therapy

  6. New Players in the Field • 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

  7. Mechanism

  8. HIV Infection Mechanism 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. HIV Infection Mechanism • 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 NatlAcadSci USA 82 (20): 7096–100.

  10. Nucleoside Analogues • Nucleoside analogues used in HIV treatments are designed to be preferentially used by reverse transcriptase • Once inside thebody’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

  11. Nucleoside Analogue Mechanism

  12. Resistance

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

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

  15. Specific Mutations • 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 and K65R • 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.

  17. Nucleoside Analogues as HIV Treatment

  18. An example - Zidovudine (AZT) • Zidovudine (or azidothymidine, AZT), was the first antiretroviral drug approved for HIV treatment • First breakthrough in AIDS treatment, reducing virus replication significantly

  19. AZT • 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 - Pneumocycstiscarinii, 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.

  20. AZT • 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

  21. HAART • 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 303.5664 (2004):1585

  22. References • 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.

  23. Summary Slide • 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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