Timothy Clark Medicinal Chemistry

1. Human Immunodeficiency Virus (HIV) / AIDS Timothy Clark Medicinal Chemistry

2. What is HIV ? • Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS),a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth • Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell and have the unique ability among retroviruses of being able to replicate in non-dividing cells, so they are one of the most efficient methods of a gene delivery vector.

3. Helper T Cells/ CD4 T cells • HIV infects primarily vital cells in the human immune system such as helper T cells (to be specific, CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. • T helper cells (also known as Th cells) are a sub-group of lymphocytes (a type of white blood cell or leukocyte) that play an important role in establishing and maximizing the capabilities of the immune system. These cells are unusual in that they have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens, and without other immune cells they would usually be considered useless against an infection. Th cells are involved in activating and directing other immune cells, and are particularly important in the immune system. They are essential in determining B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. It is this diversity in function and their role in influencing other cells that gives T helper cells their name. Mature Th cells are believed to always express the surface protein CD4. T cells expressing CD4 are also known as CD4+ T cells.

4. Helper T Cells Function

5. Sign and Symptoms of HIV • Early Symptoms of HIVThe earliest symptoms of HIV infection occur while your body begins to form antibodies to the virus (known as seroconversion) between six weeks and three months after infection with the HIV virus. Those who do show early HIV symptoms will develop flu-like symptoms. This can include: fever, rash, muscles aches and swollen lymph nodes and glands. However, for most people, the first symptoms of HIV will not be apparent.

6. HIV/ AIDs Symptoms • Although the infection is slowly taking hold of your body, the majority of those infected with HIV will be asymptomatic. Only by being tested for HIV can you know for sure if you have been infected. Yet, despite the absence of HIV symptoms, you are still highly contagious during this time making it very much a possibility to infect others • Without treatment, people infected with HIV can expect to develop AIDS eight to ten years after HIV infection. Taking HIV medications, however, can slow down this progression. With treatment, it can take ten to 15 years or more before you develop AIDS. In the later stages of HIV, before it progresses to full blown AIDS, signs of HIV infection can involve more severe symptoms • chronic yeast infections or thrush • Fever and/or night sweats • Easy bruising • Bouts of extreme exhaustion • Unexplained body rashes • Appearance of purplish lesions on the skin or inside mouth • Sudden unexplained weight loss • Chronic diarrhea lasting for a month or more

7. AIDs Symptoms/ Opportunistic Infections Symptoms of AIDSTo be diagnosed with AIDS, your T4 cell count must drop to below 200 per cubic millimeter (in healthy adults, a T4 cell count of 1,000 or more per millimeter is normal) or be infected with an opportunistic infection. Opportunistic infections are so named because they take advantage of your weakened immune system. The Centers for Disease Control and Prevention maintains a list of those illnesses that are deemed to be opportunistic infections and lead to an AIDS diagnosis. • Kaposi's Sarcoma • Pulmonary tuberculosis • Candidiasis of the esophagus, trachea, bronchi or lungs • Toxoplasmosis of the brain • Severe bacterial infections • Invasive cervical cancer • Recurrent pneumonia Additionally, vision loss, nerve damage and brain impairment can also occur. Signs of brain deterioration include troubles thinking, loss of co-ordination and balance and behavioral changes.

8. Transmission • HIV is found in blood and other body fluids such as semen and vaginal fluids. It cannot live for long outside the body, so to be infected with HIV you need to allow some body fluid from an infected person to get inside your body. The virus can enter the body via contact with the bloodstream or by passing through delicate mucous membranes, such as inside the vagina, rectum or urethra. • The most common ways that people become infected with HIV are: • having sexual intercourse with an infected partner. • injecting drugs using a needle or syringe that has been used by someone who is infected. • as a baby of an infected mother, during pregnancy, labour or delivery, or through breastfeeding.

9. Other Problems Associated with AIDs • In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which may prompt a change of treatment. For example, an individual superinfected with two separate strains of the HIV virus may contract a strain that is resistant to antiretroviral treatment. The combined infection has also been shown to reduce the overall effectiveness of the immune response. • In medicine, superinfection is an infection following a previous infection, especially when caused by microorganisms that are resistant or have become resistant to the antibiotics used earlier. The rate of superinfection — re-infection of an HIV-positive person with a second strain of the virus — appears to be higher than previously thought, at least among gay men not on treatment.

10. HIV/AIDs Treatment • antiretroviral drug treatment • The aim of antiretroviral treatment is to keep the amount of HIV in the body at a low level. This stops any weakening of the immune system and allows it to recover from any damage that HIV might have caused already. • Taking two or more antiretroviral drugs at a time is called combination therapy. Taking a combination of three or more anti-HIV drugs is sometimes referred to as Highly Active Antiretroviral Therapy (HAART). • If only one drug was taken, HIV would quickly become resistant to it and the drug would stop working. Taking two or more antiretroviral at the same time vastly reduces the rate at which resistance would develop, making treatment more effective in the long term.

11. Groups of Antiretroviral Drugs • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors NRTIs- NRTIs interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself. • Non-Nucleoside Reverse Transcriptase Inhibitors- NNRTIs also stop HIV from replicating within cells by inhibiting the reverse transcriptase protein. • Protease Inhibitors- PIs inhibit protease, which is another protein involved in the HIV replication process. • Fusion or Entry Inhibitors- Fusion or entry inhibitors prevent HIV from binding to or entering human immune cells. • Integrase Inhibitors- Integrase inhibitors interfere with the integrase enzyme, which HIV needs to insert its genetic material into human cells.

12. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Treating HIV Link

13. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Drugs • Lamivudine, Epivir • Abacavir, Ziagen • Zidovudine, Retrovir • Stavudine, Zerit • Didanosine, Videx EC • emtricitabine, Emtriva • Tenofovir, Viread

14. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Drugs Lamivudine, Epivir Zidovudine, Retrovir

15. Non-Nucleoside Reverse Transcriptase Inhibitors

16. Non-Nucleoside Reverse Transcriptase Inhibitors Drugs • Delavirdine, Rescriptor • Efavirenz, Sustiva • Etravirine, Intelence • Nevirapine, Viramune

17. Non-Nucleoside Reverse Transcriptase Inhibitors Drugs Efavirenz, Sustiva Delavirdine, Rescriptor

18. Protease Inhibitors Drugs • Saquinavir, Fortovase • Ritonavir, Norvir • Indinavir, Crixivan • Nelfinavir, Viracept • Amprenavir, Agenerase

19. Protease Inhibitors Drugs Ritonavir

20. Fusion or Entry Inhibitors

21. Fusion or Entry Inhibitors Drugs • Enfuvirtide, Fuzeon Requires extensive patient counseling on injection technique, adherence, and management of possible side effects. • Maraviroc Many drug-drug interactions; dose adjustment needed with many other antiretrovirals and/or other medications. Consult current information before prescribing.

22. Fusion or Entry Inhibitors Drugs Maraviroc Enfuvirtide, Fuzeon

23. 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. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but they could be applied to other retroviruses. • Elvitegravir (GS 9137 or JTK-303), licensed by Gilead Sciences from Japan Tobacco, is currently undergoing Phase 2 clinical trials. GS 9137 is a low-molecular-weight, highly selective integrase inhibitor that shares the core structure of quinolone antibiotics. • MK-2048, a second generation integrase inhibitor, that appears to have a duration of action up to 4 times longer than raltegravir

24. On-Going Clinical Trials of HIV/ AIDS Clinical Trials Link

25. Assigned Reading Journal Article

26. Homework Questions • 1. Describe the differences between the HIV 1 type and HIV 2? • Draw a structure from each of the five anti- HIV drugs. (NRTIs, NNRTIs, Fusion Inhibitors, Integrase Inhibitors, and Protease Inhibitors.) • Describe the mechanism of action of NRTIs and NNRTIs, explain the similarities and differences between the two. • What is a Superinfection?

27. Resources/ Referrences • Divisions of HIV/AIDS Prevention (2003). "HIV and Its Transmission". Centers for Disease Control & Prevention. http://www.cdc.gov/HIV/pubs/facts/transmission.htm. • UNAIDS, WHO (December 2007). "2007 AIDS epidemic update" (PDF). http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf. Retrieved 2010-04-12. • "HIV/ AIDs." EMedicineHealth (2010): 1-3. WebMD. Web. 6 Apr. 2010. <www.avert.org/new-aids-drugs.hmt>. • “HIV/ AIDs” EMedicineHealth (2010): 1-5. WebMD. Web. 6 Apr. 2010 www.avert.org/aids-drugs-table.hmt • Douek DC, Roederer M, Koup RA (2009). "Emerging concepts in the immunopathogenesis of AIDS". Annu. Rev. Med.60: 471–84. • Schneider MF, Gange SJ, Williams CM, Anastos K, Greenblatt RM, Kingsley L, Detels R, Munoz A (2005). "Patterns of the hazard of death after AIDS through the evolution of antiretroviral therapy: 1984–2004". AIDS19 (17): 2009–18. • Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection (October 6, 2005). "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected • National Institutes of Health (October 15, 2006) “The HIV/ AIDs Fact Sheet”.