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HIV &HIV & TreatmentTreatment

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

OutlineOutline

Overview Content

Animal model for HIV Life Cycle of HIV Anti-HIV Drugs Combination Therapy

Summary

History of HIVHistory of HIV

Some scientists believed HIV spread from monkeys to human between 1926-1943.

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 HIVHistory 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 modelsAIDS 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 modelsTypes of AIDS animal models

Non-human primate models Chimpanzee Macaque monkeys

Murine models Transgenic mice SCID mice

Feline models Cats

Overview of HIVOverview 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 HIVOverview 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 HIVTypes 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 : is closely related to SIV

Life Cycle of HIVLife Cycle of HIV

Reverse transcriptaseI nhibitor

Protease I nhibitors

I ntegrase I nhibitors

Fusion I nhibitors

Anti-HIV DrugsAnti-HIV Drugs

Types of anti-HIV drugs Reverse Transcriptase Inhibitors

Nucleoside AnaloguesE.g. AZT, ddI, ddC and d4T

Non-nucleoside Reverse Transcriptase Inhibitors

E.g. Nevirapine, Delavirdine Protease Inhibitors

E.g. Ritonavir, Indinavir, Saquinavir

Reverse Transcriptase Reverse Transcriptase InhibitorsInhibitors

Nucleoside AnaloguesNucleoside 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 Reverse Transcriptase InhibitorsInhibitors

Non-nucleoside Reverse Non-nucleoside Reverse Transcriptase InhibitorsTranscriptase 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 EnzymeHIV 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 InhibitorsProtease 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 & IndinavirRitonavir & Indinavir

Ritonavir

- 1inhibits HIV and HIV- 2 .

ii iiiiii ii iiiiiii iiiiiiii iiiii

- no direct anti HIV effec t in the brain

Indinavir

inhibits HIV-1 protease.

is active in both acutely and chronically infected cells.

can reduce viral loads i n the nervous system.

Ritonavir

The emergence of viral resistance requires the presence of one or more mutations.

Indinavir

iii iiiiiiiii ii iiiii i esistance requires the presence of three or m

ore mutations. If resistance to IDV occ

urs, it can also increas e the probability of res

istance to other PIs.

Ritonavir & IndinavirRitonavir & 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 & IndinavirRitonavir & 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 & IndinavirRitonavir & Indinavir

Why does the combination Why does the combination therapy make sense?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 Combinations of Nucleosides AnaloguesAnalogues

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 Combinations of NRTIs and NNRTIsNNRTIs

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

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Efavirenz+zidovudine and lamivudine Efavirenz+indinavir Efavirenz+indinavir and lamivudine

Combinations of PIs and RTIsCombinations 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

SummarySummary

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.

SummarySummary

- The combinations of anti HIV drugs are used to treat AIDS patients because of their high

potency in viral suppression and a delay in d rug resistance.

Indinavir is our “CHOSEN” drug. - Engineers do not understand biology! They

chose Ritonavir.