Transcript HIV - SMU
HIV Characteristics of the virus Characteristics of the virus Icosahedra (20 sided), enveloped virus of the lentivirus subfamily of retroviruses. Two viral strands of RNA found in core surrounded by protein outer coat. Outer envelope contains a lipid matrix within which specific viral glycoproteins are imbedded. These knob-like structures responsible for binding to target cell. HIV • HIV is a RETROVIRUS. A Retrovirus is a ribonucleic acid (RNA) virus that must reverse to the Deoxyribonucleic acid (DNA) before reproducing/replicating. • It is the DNA gene that enables the Virus to replicate. HIV invades mainly the helper T cells to replicate itself. • No Cure prevalence prevalence Estimated HIV/AIDS prevalence among young adults (15-49) by country as of 2008. Stage 1 - Primary Short, flu-like illness - occurs one to six weeks after infection no symptoms at all Infected person can infect other people Stage 2 - Asymptomatic Lasts for an average of ten years This stage is free from symptoms There may be swollen glands The level of HIV in the blood drops to very low levels HIV antibodies are detectable in the blood Stage 3 - Symptomatic The symptoms are mild The immune system deteriorates emergence of opportunistic infections and cancers Stage 4 - HIV AIDS The immune system weakens The illnesses become more severe leading to an AIDS diagnosis Opportunistic Infections associated with AIDS Bacterial Tuberculosis (TB) Strep pneumonia Viral Kaposi Sarcoma Herpes Influenza (flu) Opportunistic Infections associated with AIDS Parasitic Pneumocystis Fungal Candida Cryptococcus carinii HIV/AIDS Transmission Sexual Mother-to-child Blood products Multiple infection Transmission Life Cycle of HIV There are 7 steps in the life cycle of HIV, they are Binding, Reverse transcription, Integration, Transcription, Translation, Assembly, Budding. Treatment When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART. The decision on when to start treatment should take into account , HIV viral load, treatment history, resistance profiles and patient preference. Ann. Intern. Med. 137 (5 Pt 2): 381–433. PMID 12617573 APPROACHES FOR TREATMENT OF AIDS NATURAL ANTI HIV AGENTS CHEMOKINE (CCR5 and CXCR4) RECEPTOR ANTAGONIST ANTI-SENSE OLIGONUCLEOTIDES ANTI-CD4 MONOCLONAL ANTIBODY TNX 355 NANOTECHNOLOGY FOR HIV/AIDS TREATMENT MEDICINAL CHEMISTRY FOR THE TREATMENT OF AIDS Classes of drugs Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Reverse-transcriptase inhibitor(RTI) Protease inhibitors (PIs) Integrase inhibitors Entry inhibitors (or fusion inhibitors) Maturation inhibitors Reverse-transcriptase inhibitor RTIs come in three forms: Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs) Nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs) Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) Mechanism When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying Zidovudine(Azidothymidine,AZT) AZT was the first approved treatment for HIV, sold under the names Retrovir and Retrovis. AZT use was a major breakthrough in AIDS therapy in the 1990s. AZT slows HIV spread significantly, but does not stop it entirely. World Health Organization. March 2005. Retrieved 2006-03-12 Tenofovir Tenofovir disoproxil fumarate (TDF or PMPA), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase, an enzyme crucial to viral production in HIV-infected people. Emau P, Jiang Y, Agy MB, et al. (2006). Efavirenz brand names Sustiva and Stocrin NNRTI Unlike NRTIs, which bind at the enzyme's active site, NNRTIs act allosterically by binding to a distinct site away from the active site known as the NNRTI pocket. Ren J, Bird LE, Chamberlain PP, et al. (2002). "Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to nonnucleoside inhibitors". Proc Natl Acad Sci USA 99 (22): 14410–15. doi:10.1073/pnas.222366699. PMID 12386343 Protease inhibitors (PIs) PIs prevent viral replication by inhibiting the activity of proteases Protease inhibitors were the second class of antiretroviral drugs developed. Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang and Dale's Pharmacology (6th Edition ed.). Philadelphia: Churchill Livingstone Elsevier. Saquinavir Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir inhibits both HIV-1 and HIV-2 proteases. FortovaseTM (saquinavir) soft gelatin capsules. Product information Integrase inhibitor Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Steigbigel RT, Cooper DA, Kumar PN, et al. (July 2008). Raltegravir Raltegravir (MK-0518, brand name Isentress) Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs 15 (12): 1507–22. Entry inhibitor Entry inhibitors, also known as fusion inhibitors This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to AIDS An HIV virion binds to a CD4+ human cell. The two bottom pictures depict two proposed models of HIV fusion with the cell. Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of coreceptor inhibition to counter HIV entry" (abstract page). Expert Opin Pharmacother 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538 Proteins involved in the HIV entry process. CD4, a protein receptor found on the surface of helper T cells in the human immune system, also called CD4+ T cells gp120, a protein on HIV surface that binds to the CD4 receptor CCR5, a second receptor found on the surface of CD4+ cells, called a chemokine co-receptor CXCR4, another chemokine co-receptor found on CD4+ cells "parang gago" gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane Maraviroc brand-named Selzentry, or Celsentri outside the U.S. Maraviroc is an entry inhibitor. Specifically, maraviroc is a CCR5 receptor antagonist, and binds to the chemokine receptor CCR5 and blocks the HIV gp120 (V3 loop) from associating with the receptor. HIV is then unable to bind and enter human macrophages. Levy JA (January 2009). "HIV pathogenesis: 25 years of progress and persistent challenges". AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484 CCR5-receptor antagonists Figure 1 HIV entry into CD4+ cell via CCR5 co-receptor. Maturation inhibitor Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein. Because these viral particles have a defective core, the virions released consist mainly of noninfectious particles. Alpha interferon is a currently available agent in this class. Two additional ones under investigation are bevirimat and Vivecon. Alpha Interferon Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. Liu YJ (2005). "IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors". Annu Rev Immunol 23: 275–306. The Move Toward Lower Pill Burdens Regimen Dosing 1996 Zerit/Epivir/Crixivan 10 pills, Q8H 1998 Retrovir/Epivir/Sustiva 5 pills, BID 2002 Combivir (AZT/3TC)/EFV 3 pills, BID 2003 Viread/ Emtriva/Sustiva 3 pills, QD 2004 Truvada/Sustiva 2 pills, QD Daily pill burden Reading: Thakur, D. S. et al. “Anti-HIV Agents: A Step Toward Future” International Journal of Pharmaceutical Sciences Review and Research (2010) Vol. 3, pp. 10-18. Questions: Q: What is the ETIOLOGY of AIDS? Q: How many steps are there in the life cycle of HIV and what are they? Q: What is CCR5 and how it relates with HIV? Q: In natural anti HIV agents, what structure does prostratin have and where does it comes from and how it possibly works? Q: How does maraviroc works to treat HIV? Q: Give two example of structure of classical antiretroviral agents, and what function group do you think is they have in common?