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HIV & Treatment Duangrat Inthron Duangrat Inthron Tawit Suriyo Tawit Suriyo Pronpat Intarasunanont Pronpat Intarasunanont Somjed Sahasitiwat Somjed Sahasitiwat Peerakarn Banjerdkij Peerakarn Banjerdkij Ormrat Kampeerawipakorn Ormrat Kampeerawipakorn

Outline Overview Content Animal model for HIV Life Cycle of HIV Anti-HIV Drugs Combination Therapy Summary

History of HIV Some scientists believed HIV spread from monkeys to human between In 1981, a rare cancer-Kaposi’s Sarcoma-was found in healthy gay men. This was called GRID (Gay Related Immune Deficiency). In 1982, the Gay Men Heath Crisis was found in New York City.

History of HIV The term AIDS or Acquired Immune Deficiency Syndrome was used for the first time in 1982 In 1983, HIV or Human Immunodeficiency Virus (HIV) was first identified. 4,749 cases of AIDS in the U.S. and 2,112 died in 1983

AIDS Animal models useful for studying HIV infection help scientists to know about HIV genetics and mechanism of pathogenesis including developing potent anti-HIV drugs and vaccines to suppress HIV replication

Types of AIDS animal models Non-human primate models Chimpanzee Macaque monkeys Murine models Transgenic mice SCID mice Feline models Cats

Overview of HIV HIV is a lentivirus, a class of retrovirus. HIV can infect a number of different cells within the host such as: CD4 lymphocytes (T-helper lymphocytes) Monocytes and Macrophages Dendritic cells (Lymph node and Central nervous system)

Overview of HIV During HIV infection, the number of CD4 lymphocytes in blood progressively declines. Because of the reduction, AIDS patients become ill and eventually die from the opportunistic infections and cancers such as Pneumocyatis carnii together with Herpes simplex, cytomagalovirus and candida Kaposi’s sarcoma Lymphomas

Types of HIV HIV type 1 (HIV-1) : is a cause of the current pandemic HIV type 2 (HIV-2) : is found in West Africa but rarely elsewhere : i s closely related to SIV

Life Cycle of HIV

Anti-HIV Drugs Types of anti-HIV drugs Reverse Transcriptase Inhibitors Nucleoside Analogues E.g. AZT, ddI, ddC and d4T Non-nucleoside Reverse Transcriptase Inhibitors E.g. Nevirapine, Delavirdine Protease Inhibitors E.g. Ritonavir, Indinavir, Saquinavir

Reverse Transcriptase Inhibitors Nucleoside Analogues Nucleoside Analogues are both inhibitors and substrates of RT need metabolism before function competitive inhibition with natural dNTP incorporate into the growing viral DNA leads to DNA chain termination

Reverse Transcriptase Inhibitors Non-nucleoside Reverse Transcriptase Inhibitors Non-nucleoside Reverse Transcriptase Inhibitors structurally heterogeneous selectively inhibit HIV-1 replication do not need metabolism before function interact with a non-substrate binding site non-competitive inhibitors

HIV Protease Enzyme is an aspartyl protease consists of 99 amino acids exists as a C2-symmetric homodimer with a single active site catalytic site contains catalytic triads (Asp-Thr- Gly) cleaves polyproteins to functional proteins

Protease Inhibitors slow down the action of HIV protease interact with catalytic residues and displace a structural water molecule lack cross-reactivity with human protease enzyme

Ritonavir & Indinavir Ritonavir inhibits HIV-1 and HIV- 2 protease. is active in acutely infected cells no direct anti-HIV effect in the brain Indinavir inhibits HIV-1 protease. is active in both acutely and chronically infected cells. can reduce viral loads in the nervous system.

Ritonavir The emergence of viral resistance requires the presence of one or more mutations. Indinavir The emergence of viral resistance requires the presence of three or more mutations. If resistance to IDV occurs, it can also increase the probability of resistance to other PIs. Ritonavir & Indinavir

Ritonavir Drug Interaction: increases plasma level of drugs that are metabolized by CYP- 450, Indinavir Drug Interaction: plasma level of IDV can alter when it’s taken with drugs that can inhibit or enhance activity of CYP-450 Ritonavir & Indinavir

Ritonavir Side Effects : - nausea, vomiting,diarrhea - numbness, tangling and burning sensation - allergic reaction - increase liver toxicity Indinavir Side Effects: - nausea,vomiting,diarrhea - Kidney Stones - Hyperbilirubinemia Ritonavir & Indinavir

Why does the combination therapy make sense? Combination therapy can decrease HIV progression better than monotherapy. Different anti-HIV drugs can attack the virus in different ways. Different drugs can attack virus in different types of cells and in different parts of the body. Combinations of anti-HIV drugs may overcome or delay resistance.

Combinations of Nucleosides Analogues Based on differences in the intracellular activity, NRTIs that work in actively infected cells are given with those that work in resting cells. ACTG 175 trial showed the CD4 cell count increased significantly in the combinations of AZT/ddI and AZT/ddC group, compared with AZT monotherapy.

Combinations of NRTIs and NNRTIs NNRTIs have same target and activity as in NRTIs. The incorporation of NRTIs and NNRTIs shows synergistic effect and is active against AZT- resistant HIV isolates.

Combination of NRTIs/NNRTIs can reduce HIV- 1 RNA level

Combinations of PIs and RTIs Protease inhibitors were used in combination with nucleoside analogues. The triple drugs (PIs+2 NRTIs) given together resulted in a large and longer-lasting reduction in the amount of virus in blood compared with 2 NRTIs combinations or with PIs alone.

IDV/AZT/3TC IDV AZT/3TC Combination of PI/NRTI can reduce HIV RNA levels

Summary Anti-HIV drugs are developed by targeting the various stages of HIV’s life cycle, e.g., RTIs inhibit RT enzyme in the early stage of replication. Initially, a single anti-HIV drug was used to treat patient living with AIDS, but it was not successful because of frequent development of viral resistance to anti-HIV drugs.

Summary The combinations of anti-HIV drugs are used to treat AIDS patients because of their high potency in viral suppression and a delay in drug resistance. Indinavir is our “CHOSEN” drug. Engineers do not understand biology! - They chose Ritonavir.